Alcohol derivatives as kv7 potassium channel openers

ABSTRACT

The present invention provides novel compounds which activate the Kv7 potassium channels. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders responsive to the activation of Kv7 potassium channels.

FIELD OF THE INVENTION

The present invention relates to novel compounds which activate the Kv7potassium channels. Separate aspects of the invention are directed topharmaceutical compositions comprising said compounds and uses of thecompounds to treat disorders responsive to the activation of Kv7potassium channels

BACKGROUND OF THE INVENTION

Voltage-dependent potassium (Kv) channels conduct potassium ions (K+)across cell membranes in response to changes in the membrane potentialand can thereby regulate cellular excitability by modulating (increasingor decreasing) the electrical activity of the cell. Functional Kvchannels exist as multimeric structures formed by the association offour alpha and four beta subunits. The alpha subunits comprise sixtransmembrane domains, a pore-forming loop and a voltage-sensor and arearranged symmetrically around a central pore. The beta or auxiliarysubunits interact with the alpha subunits and can modify the propertiesof the channel complex to include, but not be limited to, alterations inthe channel's electrophysiological or biophysical properties, expressionlevels or expression patterns.

Nine Kv channel alpha subunit families have been identified and aretermed Kv1-Kv9. As such, there is an enormous diversity in Kv channelfunction that arises as a consequence of the multiplicity ofsub-families, the formation of both homomeric and heteromeric subunitswithin sub-families and the additional effects of association with betasubunits (Christie, 25 Clinical and Experimental Pharmacology andPhysiology, 1995, 22, 944-951).

The Kv7 channel family consists of at least five members which includeone or more of the following mammalian channels: Kv7.1, Kv7.2, Kv7.3,Kv7.4, Kv7.5 and any mammalian or non-mammalian equivalent or variant(including splice variants) thereof. Alternatively, the members of thisfamily are termed by the gene name KCNQ1, KCNQ2, KCNQ3, KCNQ4 and KCNQ5respectively (Dalby-Brown, et al., Current Topics in MedicinalChemistry, 2006, 6, 9991023).

As mentioned above, the neuronal Kv7 potassium channels play roles incontrolling neuronal excitation. Kv7 channels, in particular Kv7.2/Kv7.3heterodimers, underlie the M-current (Wang et al Science. 1998 Dec. 4;282(5395):1890-3). The M-current has a characteristic time- andvoltage-dependence that results in stabilisation of the membranepotential in response to multiple excitatory stimuli.

In this way, the M-current is involved in controlling neuronalexcitability (Delmas & Brown, Nature, 2005, 6, 850-862). The M-currentis a non-inactivating potassium current found in many neuronal celltypes. In each cell type, it is dominant in controlling membraneexcitability by being the only sustained current in the range of actionpotential initiation (Marrion, Annual Review Physiology 1997, 59,483-504).

Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acidethyl ester) is a compound which binds to the Kv7 potassium channels(Wuttke, et al., Molecular Pharmacology, 2005, 67, 1009-1017).Retigabine activates K⁺ current in neuronal cells and the pharmacologyof this induced current displays concordance with the publishedpharmacology of the M-channel that has been correlated to the Kv7.2/3 K⁺channel heteromultimer which suggests that activation of Kv7.2/3channels is responsible for at least some of the anticonvulsant activityof this agent (Wickenden, et al., Molecular Pharmacology 2000, 58,591-600). Retigabine is effective in reducing the incidence of seizuresin epileptic patients (Bialer, et al., Epilepsy Research 2002, 51,31-71). Retigabine has a broad spectrum and potent anticonvulsantproperties. It is active after oral and intraperitoneal administrationin rats and mice in a range of anticonvulsant tests (Rostock, et al.,Epilepsy Research 1996, 23, 211-223).

The five members of this family differ in their expression patterns. Theexpression of Kv7.1 is restricted to the heart, peripheral epithelialand smooth muscle, whereas the expression of Kv7.2, Kv7.3, Kv7.4 andKv7.5 appear to be dominant in the nervous system which includes thehippocampus, cortex, ventral tegmental area, and dorsal root ganglionneurons (for a review see Greene & Hoshi, Cellular and Molecular LifeSciences, 2017, 74(3), 495-508).

The KCNQ2 and KCNQ3 genes appear to be mutated in an inherited form ofepilepsy known as benign familial neonatal convulsions (Rogawski, Trendsin Neurosciences 2000, 23, 393-398). The proteins encoded by the KCNQ2and KCNQ3 genes are localised in the pyramidal neurons of the humancortex and hippocampus, regions of the brain associated with seizuregeneration and propagation (Cooper et al., Proceedings National Academyof Science USA 2000, 97, 4914-4919).

Furthermore, mRNA for Kv7.3 and 5, in addition to that for Kv7.2, areexpressed in astrocytes and glial cells. Thus Kv7.2, Kv7.3 and Kv7.5channels may help modulate synaptic activity in the CNS and contributeto the neuroprotective effects of KCNQ channel openers (Noda, et al.,Society for Neuroscience Abstracts 2003, 53.9), which would be relevantfor the treatment of neurodegenerative disorders such as but not limitedto Alzheimer's disease, Parkinson's disease and Huntington's chorea.

mRNA for Kv7.2 and Kv7.3 subunits are found in brain regions associatedwith anxiety and emotional behaviours such as depression and bipolardisorder e.g. hippocampus, ventral tegmental area and amygdala(Saganich, et al. Journal of Neuroscience 2001, 21, 4609-4624; Friedmanet al., Nat Commun. 2016; 7: 11671.), and retigabine is reportedlyactive in animal models of anxiety-like behaviour (Korsgaard et al JPharmacol Exp Ther. 2005 July; 314(1):282-92. Epub 2005 Apr. 6.). Assuch Kv7 channels are relevant for the treatment of emotional relateddisorders such as but not limited to bipolar depression, majordepression, anxiety, suicide, panic attacks, social phobia.

Kv7.2/3 channels have also been reported to be upregulated in models ofneuropathic pain (Wickenden, et al., Society for Neuroscience Abstracts2002, 454.7), and potassium channel modulators have been hypothesised tobe active in both neuropathic pain and epilepsy (Schroder, et al.,Neuropharmacology 2001, 40, 888-898). In addition to a role inneuropathic pain, the expression of mRNA for Kv7.2-5 in the trigeminaland dorsal root ganglia and in the trigeminal nucleus caudalis impliesthat openers of these channels may also affect the sensory processing ofmigraine pain (Goldstein, et al. Society for Neuroscience Abstracts2003, 53.8). Taken together, this evidence points to the relevance ofKCNQ channel openers for the treatment of chronic pain and neuropathyrelated disorders.

WO 07/90409 relates to the use of Kv7 channel openers for the treatmentof schizophrenia. Kv7 channel openers modulate the function of thedopaminergic system (Friedman et al., Nat Commun. 2016; Scotty et al JPharmacol Exp Ther. 2009 March; 328(3):951-62. doi:10.1124/jpet.108.146944. Epub 2008 Dec. 19; Koyama et al., JNeurophysiol. 2006 August; 96 (2):535-43. Epub 2006 Jan. 4; Li et al BrJ Pharmacol. 2017 December; 174(23):4277-4294. doi: 10.1111/bph.14026.Epub 2017 Oct. 19; Hansen et al J Pharmacol Exp Ther. 2006 September;318(3):1006-19. Epub 2006 Jun. 14) which would be relevant for thetreatment of psychiatric disorders such as but not limited to psychosis,mania, stress-related disorders, acute stress reactions, attentiondeficit/hyperactivity disorder, posttraumatic stress disorder, obsessivecompulsive disorder, impulsivity disorders, personality disorders,schizotypical disorder, aggression, autism spectrum disorders. WO01/96540 discloses the use of modulators of the M-current formed byexpression of KCNQ2 and KCNQ3 genes for insomnia, while WO 01/092526discloses that modulators of Kv7.5 can be utilized for the treatment ofsleep disorders. WO 09/015667 discloses the use of Kv7 openers in thetreatment of sexual dysfunction.

Although patients suffering from the above mentioned disorders may haveavailable treatment options, many of these options lack the desiredefficacy and are accompanied by undesired side effects. Therefore, anunmet need exists for novel therapies for the treatment of saiddisorders.

In an attempt to identify new therapies, the inventors have identified aseries of novel compounds as represented by Formula I which act asKv7.2, Kv7.3, Kv7.4 and Kv7.5 channel openers. Accordingly, the presentinvention provides novel compounds as medicaments for the treatment ofdisorders which are modulated by the KCNQ potassium channels.

SUMMARY OF THE INVENTION

The present invention relates to a compound of Formula I

-   -   wherein    -   R1 is selected from the group consisting of C₁-C₆ alkyl, CF₃,        CH₂CF₃, CF₂CHF₂, C₃-C₈ cycloalkyl, wherein said C₃-C₈ cycloalkyl        may be substituted with 1 or 2 F, CHF₂ or CF₃, and R2 is H,        C₁-C₆ alkyl or CF₃;    -   or    -   R1 and R2 combine to form C₃-C₅ cycloalkyl optionally        substituted with F, CHF₂ or CF₃;    -   R3 is C₁-C₃ alkyl or CH₂O—C₁₋₃ alkyl, optionally substituted        with F;    -   R4 is selected from the group consisting of OCF₃, OCH₂CF₃ or        OCHF₂;

The invention also concerns a pharmaceutical composition comprising acompound according to the invention and a pharmaceutically acceptablecarrier or excipient.

Furthermore, the invention concerns a method of treating a patient asdescribed in the claims and embodiments and includes treatments ofpatients suffering from epilepsy, a bipolar disorder, migraine andschizophrenia comprising administering to the subject a therapeuticallyeffective amount of the compound according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

R4 is according to an embodiment of the invention OCF₃ or OCHF₂ and

R2 is according to another embodiment H or CH₃.

In one embodiment R1 is C₃-C₄ cycloalkyl optionally substituted with 1or 2 F, CHF₂ or CF₃.

According to a specific embodiment R1 is t-butyl and R2 is H and R4 isone of OCF₃, OCH₂CF₃ or OCHF₂.

According to another specific embodiment R1 and R2 combine to formcyclobutyl optionally substituted with 1 or 2 F and R4 is one of OCF₃,OCH₂CF₃ or OCHF₂

According to a specific embodiment of the invention the compoundaccording to the invention is selected from the group consisting of:

-   (S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,-   (R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,-   (S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,-   (R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,-   (S)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,-   (R)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,-   (S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide,-   (R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide,-   (S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,-   (R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,-   (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,-   (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoro    methoxy)phenyl)ethyl)propanamide,-   (S)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,-   (R)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,-   (S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)propanamide,-   (R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,-   (R)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,-   (S)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,-   (S)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,-   (R)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentan    amide,-   N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethylpentanamide,-   N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(S)-hydroxy-4,4-dimethylpentanamide,-   (S)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide,-   (R)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide,-   (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,-   (S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide,-   (3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,-   (3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,-   4,4,4-Trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide,-   (R)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,-   (S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,-   (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,-   (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoro    methoxy)phenyl)ethyl)pentanamide,-   (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide,-   (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamide,-   (R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,-   (R)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,-   (S)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,-   (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxyphenyl)ethyl)butanamide,    AND-   (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

Reference to compounds encompassed by the present invention includesracemic mixtures of the compounds, optical isomer of the compounds forwhich this is relevant, and polymorphic and amorphic forms of compoundsof the present invention, as well as tautomeric forms the compounds forwhich this is relevant. Furthermore, the compounds of the presentinvention may potentially exist in unsolvated as well as in solvatedforms with pharmaceutically acceptable solvents such as water, ethanoland the like. Both solvated and unsolvated forms of the compounds areencompassed by the present invention.

The compound according to the invention may be in a pharmaceuticalcomposition comprising the compound and a pharmaceutically acceptableexcipient or carrier.

In one embodiment, the invention relates to a compound according to theinvention for use in therapy.

In another embodiment the invention relates to a method of treating apatient in the need thereof suffering from epilepsy, bipolar disorder,migraine or schizophrenia comprising administering to the subject atherapeutically effective amount of a compound according to theinvention

In yet another embodiment the invention relates to a method of treatinga patient in the need thereof suffering from psychosis, mania,stress-related disorders, acute stress reactions, bipolar depression,major depression, anxiety, panic attacks, social phobia, sleepdisturbances, ADHD, PTSD, OCD, impulsivity disorders, personalitydisorders, schizotypical disorder, aggression, chronic pain, neuropathy,autism spectrum disorders, Huntingtons chorea, sclerosis, multiplesclerosis, alzhiemers disease comprising administering to the subject atherapeutically effective amount of a compound according to theinvention

According to an embodiment the compounds of the invention is used intherapy.

The use of a compound according to the invention is for the treatment ofepilepsy, bipolar disorder, migraine or schizophrenia or in anotherembodiment for the treatment of psychosis, mania, stress-relateddisorders, acute stress reactions, bipolar depression, major depression,anxiety, panic attacks, social phobia, sleep disturbances, ADHD, PTSD,OCD, impulsivity disorders, personality disorders, schizotypicaldisorder, aggression, chronic pain, neuropathy, autism spectrumdisorders, Huntingtons chorea, sclerosis, multiple sclerosis, alzhiemersdisease.

In another embodiment, the compound of the invention is for themanufacture of a medicament for treating epilepsy, bipolar disorder,migraine or schizophrenia or in another embodiment for the manufactureof a medicament for treating psychosis, mania, stress-related disorders,acute stress reactions, bipolar depression, major depression, anxiety,panic attacks, social phobia, sleep disturbances, ADHD, PTSD, OCD,impulsivity disorders, personality disorders, schizotypical disorder,aggression, chronic pain, neuropathy, autism spectrum disorders,Huntingtons chorea, sclerosis, multiple sclerosis, alzhiemers disease.

In the present context, “optionally substituted” means that theindicated moiety may or may not be substituted, and when substituted ismono- or di-substituted. It is understood that where no substituents areindicated for an “optionally substituted” moiety, then the position isheld by a hydrogen atom.

A given range may interchangeably be indicated with “-” (dash) or “to”,e.g. the term “C₁₋₃ alkyl” is equivalent to “C₁ to C₃ alkyl”.

The terms “C₁-C₃ alkyl” and “C₁-C₆ alkyl” refer to an unbranched orbranched saturated hydrocarbon having from one up to six carbon atoms,inclusive. Examples of such groups include, but are not limited to,methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl and t-butyl.

The term “C₁-C₃ alkoxy” refers to a moiety of the formula —OR, wherein Rindicates C₁-C₃ alkyl as defined above.

The terms “C₃-C₆ cycloalkyl”,” C₃-C₅ cycloalkyl” or “C₃-C₈ cycloalkyl”refers to a saturated monocylic ring. Examples of such groups includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

Administration Routes:

Pharmaceutical compositions comprising a compound of the presentinvention defined above, may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,buccal, sublingual, transdermal and parenteral (e.g. subcutaneous,intramuscular, and intravenous) route; the oral route being preferred.

It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

Pharmaceutical Formulations and Excipients:

In the following, the term, “excipient” or “pharmaceutically acceptableexcipient” refers to pharmaceutical excipients including, but notlimited to, fillers, antiadherents, binders, coatings, colours,disintegrants, flavours, glidants, lubricants, preservatives, sorbents,sweeteners, solvents, vehicles and adjuvants.

The present invention also provides a pharmaceutical compositioncomprising a compound according to the invention, such as one of thecompounds disclosed in the Experimental Section herein. The presentinvention also provides a process for making a pharmaceuticalcomposition comprising a compound according to the invention. Thepharmaceutical compositions according to the invention may be formulatedwith pharmaceutically acceptable excipients in accordance withconventional techniques such as those disclosed in Remington, “TheScience and Practice of Pharmacy”, 22^(th) edition (2012), Edited byAllen, Loyd V., Jr.

Pharmaceutical compositions for oral administration include solid oraldosage forms such as tablets, capsules, powders and granules; and liquidoral dosage forms such as solutions, emulsions, suspensions and syrupsas well as powders and granules to be dissolved or suspended in anappropriate liquid.

Solid oral dosage forms may be presented as discrete units (e.g. tabletsor hard or soft capsules), each containing a predetermined amount of theactive ingredient, and preferably one or more suitable excipients. Whereappropriate, the solid dosage forms may be prepared with coatings suchas enteric coatings or they may be formulated so as to provide modifiedrelease of the active ingredient such as delayed or extended releaseaccording to methods well known in the art. Where appropriate, the soliddosage form may be a dosage form disintegrating in the saliva, such asfor example an orodispersible tablet.

Examples of excipients suitable for solid oral formulation include, butare not limited to, microcrystalline cellulose, corn starch, lactose,mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin,talcum, gelatin, pectin, magnesium stearate, stearic acid and loweralkyl ethers of cellulose. Similarly, the solid formulation may includeexcipients for delayed or extended release formulations known in theart, such as glyceryl monostearate or hypromellose. If solid material isused for oral administration, the formulation may for example beprepared by mixing the active ingredient with solid excipients andsubsequently compressing the mixture in a conventional tabletingmachine; or the formulation may for example be placed in a hard capsulee.g. in powder, pellet or mini tablet form. The amount of solidexcipient will vary widely but will typically range from about 25 mg toabout 1 g per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs,syrups, oral drops or a liquid filled capsule. Liquid oral dosage formsmay also be presented as powders for a solution or suspension in anaqueous or non-aqueous liquid. Examples of excipients suitable forliquid oral formulation include, but are not limited to, ethanol,propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol,poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palmoil, and water. Liquid oral dosage forms may for example be prepared bydissolving or suspending the active ingredient in an aqueous ornon-aqueous liquid, or by incorporating the active ingredient into anoil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations,such as colourings, flavourings and preservatives etc.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous solutions, dispersions, suspensions oremulsions for injection or infusion, concentrates for injection orinfusion as well as sterile powders to be reconstituted in sterilesolutions or dispersions for injection or infusion prior to use.Examples of excipients suitable for parenteral formulation include, butare not limited to water, coconut oil, palm oil and solutions ofcyclodextrins. Aqueous formulations should be suitably buffered ifnecessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories,inhalants, creams, gels, dermal patches, implants and formulations forbuccal or sublingual administration.

It is requisite that the excipients used for any pharmaceuticalformulation comply with the intended route of administration and arecompatible with the active ingredients.

Doses:

In one embodiment, the compound of the present invention is administeredin an amount from about 0.001 mg/kg body weight to about 100 mg/kg bodyweight per day. In particular, daily dosages may be in the range of 0.01mg/kg body weight to about 50 mg/kg body weight per day. The exactdosages will depend upon the frequency and mode of administration, thegender, the age, the weight, and the general condition of the subject tobe treated, the nature and the severity of the condition to be treated,any concomitant diseases to be treated, the desired effect of thetreatment and other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 0.1-1000 mg/dayof a compound of the present invention, such as 1-500 mg/day, such as1-100 mg/day or 1-50 mg/day. Conveniently, the compounds of theinvention are administered in a unit dosage form containing saidcompounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.

Isomeric and Tautomeric Forms:

When compounds of the present invention contain one or more chiralcenters reference to any of the compounds will, unless otherwisespecified, cover the enantiomerically or diastereomerically purecompound as well as mixtures of the enantiomers or diastereomers in anyratio.

MDL Enhanced Stereo representation is used to describe unknownstereochemistry of the compounds of the invention. Hence, the label“or1” on a chiral carbon atom is used to indicate that the absolutestereoconformation at this atom is not known; e.g. thestereoconformation at this carbon atom is either (S) or (R).Furthermore, the chiral bond from a carbon atom labelled “or1”, usingupward wedge or downward wedge, are equal representations; e.g. the twodrawings have the same meaning, the meaning being that the absolutestereoconformation at the “or1” labelled carbon atom is not known andcan be (S) or (R).Thus, the use of upward wedge bonds and downward wedge bonds from atomslabelled “or1”, are merely intended to provide a visual cue that thedrawings represent different stereoisomers, in which the conformation atthe “or1” labelled carbon atom is not known.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

Therapeutically Effective Amount:

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to alleviate, arrest, partly arrest,remove or delay the clinical manifestations of a given disease and itscomplications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician.

Treatment and Treating:

In the present context, “treatment” or “treating” is intended toindicate the management and care of a patient for the purpose ofalleviating, arresting, partly arresting, removing or delaying progressof the clinical manifestation of the disease. The patient to be treatedis preferably a mammal, in particular a human being.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference in their entirety andto the same extent as if each reference were individually andspecifically indicated to be incorporated by reference and were setforth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including “forinstance”, “for example”, “e.g.”, and “as such”) in the presentspecification is intended merely to better illuminate the invention, anddoes not pose a limitation on the scope of invention unless otherwiseindicated.

The citation and incorporation of patent documents herein is done forconvenience only, and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The present invention includes all modifications and equivalents of thesubject-matter recited in the claims appended hereto, as permitted byapplicable law.

FURTHER EMBODIMENTS OF THE INVENTION

-   1. A compound of formula Formula I

-   -   wherein    -   R1 is selected from the group consisting of C₁-C₆ alkyl, CF₃,        CH₂CF₃, CF₂CHF₂, C₃-C₈ cycloalkyl, wherein said C₃-C₈ cycloalkyl        may be substituted with 1 or 2 F, CHF₂ or CF₃, and R2 is H,        C₁-C₆ alkyl or CF₃;    -   or    -   R1 and R2 combine to form C₃-C₈ cycloalkyl optionally        substituted with 1 or 2 F, CHF₂ or CF₃;    -   R3 is C₁-C₃ alkyl or CH₂O—C₁₋₃ alkyl, said C₁-C₃ alkyl or        CH₂O—C₁₋₃ alkyl may optionally be substituted with 1 or 2 F;    -   R4 is selected from the group consisting of C₁-C₆ alkoxy, OCF₃,        OCH₂CF₃, OCHF₂, CF₃.

-   2. The compound according to embodiment 1, wherein R4 is OCF₃ or    OCHF₂.

-   3. The compound according to any of the previous embodiments,    wherein R2 is H or CH₃.

-   4. The compound according to any of the previous embodiments,    wherein R3 is CH₂O—C₁₋₃ alkyl.

-   5. The compound according to any of the previous embodiments,    wherein R1 is C₃-C₄ cycloalkyl optionally substituted with 1 or 2 F,    CHF₂ or CF₃.

-   6. The compound according to any of the previous embodiments,    wherein R1 is t-butyl and R2 is H and R4 is OCF₃, OCH₂CF₃, OCHF₂ or    CF₃.

-   7. The compound according to any of the previous embodiments,    wherein R1 and R2 combine to form a cyclobutyl optionally    substituted with 1 or 2 F and R4 is OCF₃, OCH₂CF₃, OCHF₂ or CF₃.

-   8. The compound according to embodiment 1, wherein the compound is    selected from the group consisting of:

-   (S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,

-   R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,

-   (S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,

-   (R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,

-   (S)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,

-   (R)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,

-   (S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

-   (R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide,

-   (S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,

-   (R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,

-   (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,

-   (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,

-   (S)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,

-   (R)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,

-   (S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)propanamide,

-   (R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,

-   (R)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,

-   (S)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,

-   (S)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

-   (R)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

-   N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethylpentanamide,

-   N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(S)-hydroxy-4,4-dimethylpentanamide,

-   (S)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide,

-   (R)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide,

-   (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,

-   (S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide,

-   (3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,

-   (3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,

-   4,4,4-Trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide,

-   (R)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

-   (S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

-   (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

-   (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoro    methoxy)phenyl)ethyl)pentanamide,

-   (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide,

-   (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamide,

-   (R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,

-   (R)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,

-   (S)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,

-   (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,    AND

-   (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

-   9. A method of treating a subject suffering from a disease or    disorder selected from the group consisting of epilepsy, a bipolar    disorder, migraine and schizophrenia, psychosis, mania,    stress-related disorders, acute stress reactions, bipolar    depression, major depression, anxiety, panic attacks, social phobia,    sleep disturbances, ADHD, PTSD, OCD, impulsivity disorders,    personality disorders, schizotypical disorder, aggression, chronic    pain, neuropathy, autism spectrum disorders, Huntingtons chorea,    sclerosis, multiple sclerosis, Alzhiemers Disease comprising    administering to the subject a therapeutically effective amount of    the compound of embodiments 1-8

-   10. Use of a compound disclosed in embodiments 1 to 8 in therapy.

-   11. Use of a compound disclosed in embodiments 1 to 8 for the    treatment of epilepsy, bipolar disorder, migraine or schizophrenia.

-   12. Use of a compound disclosed in embodiments 1 to 8 for the    treatment of psychosis, mania, stress-related disorders, acute    stress reactions, bipolar depression, major depression, anxiety,    panic attacks, social phobia, sleep disturbances, ADHD, PTSD, OCD,    impulsivity disorders, personality disorders, schizotypical    disorder, aggression, chronic pain, neuropathy, autism spectrum    disorders, Huntingtons chorea, sclerosis, multiple sclerosis,    alzhiemers disease.

-   13. A compound disclosed in embodiments 1 to 8 for the manufacture    of a medicament for treating epilepsy, bipolar disorder, migraine or    schizophrenia.

-   14. A compound disclosed in embodiments 1 to 8 for the manufacture    of a medicament for treating psychosis, mania, stress-related    disorders, acute stress reactions, bipolar depression, major    depression, anxiety, panic attacks, social phobia, sleep    disturbances, ADHD, PTSD, OCD, impulsivity disorders, personality    disorders, schizotypical disorder, aggression, chronic pain,    neuropathy, autism spectrum disorders, Huntingtons chorea,    sclerosis, multiple sclerosis, alzhiemers disease

EXPERIMENTAL SECTION

Biological Evaluation:

Cell Culture

A synthesized cDNA fragment encoding human Kv7.3 and human Kv7.2separated by a P2A sequence was inserted into the pcDNA5/FRT/TO vectorusing the BamHI and XhoI restriction sites. The construct was thentransfected into HEK Flp-In 293 cells using Lipofectamine2000. Thetransfected cells were grown for 48 hours in DMEM containing 10% (v/v)FBS and 1% PenStrep and subsequently maintained under selection in DMEMcontaining 10% (v/v) FBS, 1% PenStrep and 200 ug/mL Hygromycin B at 37°C. in a humidified atmosphere of 5% CO₂. The resultant stablehKv7.2/hKv7.3 cell line (HEK-hKv7.2/hKv7.3) was functionally tested withautomated whole cell patch-clamp and displayed a typical Kv7-currentwhich was sensitive to XE991 and potentiated by Retigabine.

Thallium Influx Assay

The thallium influx assay for potassium channel activation was performedanalogously to a published procedure (C. D. Weaver, et al., J BiomolScreen 2004, 9, 671-677) using the FLIPR Potassium Assay kit (MolecularDevices). HEK-hKv7.2/hKv7.3 cells were plated onto 96-well,black-walled, clear-bottomed culture plates (Corning, Acton, Mass., USA)at a density of 80,000 cells/well (100 μl/well) if the cells wereassayed the following day, or 40,000 cells/well (100 μl/well) if thecells were assayed two days after seeding.

On the assay day, the medium was removed after which 50 uL/well of testcompound diluted to 2× final concentration in HBSS containing 20 mMHEPES, and 50 uL/well of 2× dye load buffer were added. The cells werethen incubated for 60 min at room temperature in the dark. Chloride-freestimulation buffer containing Tl⁺ and K⁺ at 5× final concentration (5×concentration: 5 mM in both cases) and test compound at 1× finalconcentration, were prepared during the incubation. The cells were thenassayed in a FDSS7000EX Functional Drug Screening System (Hamamatsu).Following 60 sec of baseline fluorescence signal reading at 0.1 Hz, and10 sec at 1 Hz, 25 uL/well of stimulation buffer were added and thefluorescence continuously measured for 50 sec at 1 Hz followed, by 4 minat 0.1 Hz. Compound effect was quantified using AUC as readout andnormalized to a reference compound, which was included on each plate.

Compound Effects

In the assay described above, the compounds of the invention had thefollowing biological activity:

Example EC₅₀, nM  1a 680  1b 3300  2a 460  2b 1800  3a 11000  3b 1500 4a 11000  4b 1200  5 1800  6 3000  7a 220  7b 1500  8a 430  8b 3000  9560 10a 650 10b 1300 11a 1500 11b 4500 12a 1600 12b 5900 13a 1900 13b2900 14a 2000 14b 6600 15a 2100 15b 11000 16a 3000 16b 10000 17 2500 18a1300 18b 7100 19a 1700 19b 3400 20a 3100 20b 14000 21a 3500 21b 250

Synthesis of the Compounds of the Invention

General Methods:

¹H NMR spectra were recorded at 400.13 MHz on a Bruker Avance III 400instrument or at 300.13 MHz on a Bruker Avance 300 instrument.Deuterated dimethyl sulfoxide or deuterated chloroform was used assolvent. Tetramethylsilane was used as internal reference standard.Chemical shift values are expressed in ppm-values relative totetramethylsilane. The following abbreviations are used for multiplicityof NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet,h=heptet, dd=double doublet, ddd=double double doublet, dt=doubletriplet, dq=double quartet, tt=triplet of triplets, m=multiplet andbrs=broad singlet.

Chromatographic systems and methods to evaluate chemical purity (LCMSmethods) and chiral purity (SFC and HPLC methods) are described below.

LCMS Method 1: Apparatus: Agilent 1200 LCMS System with ELS Detector.

Column Waters Xbridge-C18, 50 × 2 mm, 5 μm Flow rate 0.8 mL/min Run time4.5 min. Wavelength 254 nm Column temp 50° C. Ion source ESI Solvent AWater + 0.04% TEA Solvent B MeCN + 0.02% TEA Gradient Time (min) A % B %0 99 1 3.4 0 100 4 99 1 4.5 99 1

LCMS Method 2: Apparatus: Agilent 1200 LCMS System with ELS Detector

Column Phenomenex Luna-C18, 50 × 2 mm, 5 μm Flow rate 0.8 mL/min Runtime 4.5 min. Wavelength 254 nm Column temp 50° C. Ion source ESISolvent A Water + 0.1% TEA Solvent B MeCN + 0.05% TEA Gradient Time(min) A % B % 0 99 1 3.4 0 100 4 99 1 4.5 99 1

LCMS Method 3: Apparatus Agilent 1200 LCMS System with ELS Detector

Column Waters XBridge ShieldRP18, 50 × 2.1 mm, 5 μm Flow rate 0.8 mL/minRun time 4.5 min. Wavelength 254 nm Column temp 40° C. Ion source ESISolvent A Water + 0.05% NH₃•H₂O Solvent B MeCN Gradient Time (min) A % B% 0 95 5 3.4 0 100 4 0 100 4.5 95 5

LCMS Method 4 Apparatus Agilent 1200 LCMS System with ELS Detector

Column Phenomenex Luna-C18, 50 × 2 mm, 5 μm Flow rate 0.8 mL/min Runtime 4.5 min. Wavelength 254 nm Column temp 50° C. Ion source ESISolvent A Water + 0.1% TEA Solvent B MeCN + 0.05% TEA Gradient Time A %B % 0 90 10 3.4 0 100 4 0 100 4.01 90 10 4.5 90 10

LCMS Method 5: Apparatus Agilent 1200 LCMS System with ELS Detector

Column Waters Xbridge-C18, 50 × 2 mm, 5 μm Flow rate 0.8 mL/min Run time4.5 min. Wavelength 254 nm Column temp 50° C. Ion source ESI Solvent AWater + 0.04% TEA Solvent B MeCN + 0.02% TEA Gradient Time A % B % 0 9010 3.4 0 100 4 0 100 4.01 90 10 4.5 90 10

LCMS Method 6: Apparatus Agilent 1200 LCMS System with ELS Detector

Column Waters XBridge ShieldRP18, 2.1*50 mm, 5 μm Flow rate 0.8 mL/minRun time 4.5 min. Wavelength 254 nm Column temp 40° C. Ion source ESISolvent A Water + 0.05% NH₃•H₂O Solvent B MeCN Gradient Time A% B% 0 8515 3.4 0 100 4 0 100 4.01 85 15 4.5 85 15

SFC Method 1: Apparatus: Agilent 1260 with DAD Detector

Column Chiralpak AS-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 40° C. Solvent A EtOH + 0.05%diethylamine Gradient Time (min) A% 0 5 5.5 40 8.5 40 8.51 5 10 5

SFC Method 2: Apparatus: Waters UPC2

Column Chiralpak AD-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 210 nm Column temp 35° C. Solvent A EtOH + 0.05%diethylamine Gradient Time (min) A% 0 5 5 40 7.5 40 7.51 5 10 5

SFC Method 3: Apparatus: Waters UPC2

Column Chiralpak AD-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 35° C. Solvent A EtOH + 0.05%diethylamine Gradient Time (min) A% 0 5 5 5 5.01 40 7.5 40 7.01 5 10 5

SFC Method 4: Apparatus: Agilent 1260

Column Lux Cellulose-2 150 × 4.6 mm I.D., 3μm Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 40° C. Solvent A MeOH + 0.05%diethylamine Gradient Time (min) A % 0    5 5.5 40 8.5 40  8.51  5 10   5

SFC Method 5: Apparatus: Agilent 1260

Column (R, R)Whelk-01 100 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 254 nm Column temp 40° C. Solvent A EtOH + 0.05%diethylamine Gradient Time (min) A % 0    5 5.5 40 8.5 40  8.51  5 10   5

SFC Method 6: Apparatus: Waters UPC2

Column Chiralcel OD-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 35° C. Solvent A iPrOH +0.05% diethylamine Gradient Time A % 0    5 5   40 7.5 40  7.51  5 10   5

SFC method 7: Apparatus: Waters UPC2

Column Chiralcel OD-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 270 nm Column temp 35° C. Solvent A iPrOH +0.05% diethylamine Gradient Time A % 0    5 5   40 7.5 40  7.51  5 10   5

SFC Method 8: Apparatus: Agilent 1260

Column Chiralpak IC-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 40° C. Solvent A EtOH + 0.05%diethylamine Gradient Time A % 0    5 5.5 40 8.5 40  8.51  5 10    5

SFC Method 9: Apparatus: Agilent 1260

Column Lux Cellulose-2 150 × 4.6 mm I.D., 3 μm Flow rate 2.5 mL/min Runtime 10 min. Wavelength 20 nm Column temp 40° C. Solvent A iPrOH + 0.05%diethylamine Gradient Time A % 0    5 5.5 40 8.5 40  8.51  5 10    5

SFC Method 10: Apparatus: Agilent 1260

Column Chiralpak AD-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 40° C. Solvent A EtOH + 0.05%diethylamine Gradient Time A % 0    5 5.5 40 8.5 40  8.51  5 10    5

SFC Method 11: Apparatus: Waters UPC2

Column Chiralpak AS-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 35° C. Solvent A iPrOH +0.05% diethylamine Gradient Time A % 0    5 5   40 7.5 40  7.51  5 10   5

SFC Method 12: Apparatus: Agilent 1260

Column ChiralCel OJ-H 150 × 4.6 mm I.D., 5 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 40° C. Solvent A iPrOH +0.05% diethylamine Gradient Time A % 0    5 5.5 40 8.5 40  8.51  5 10   5

SFC Method 13: Apparatus: Agilent 1260

Column ChiralPak AY-3 150 × 4.6 mm I.D., 3 um Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 40° C. Solvent A EtOH + 0.05%diethylamine Gradient Time A % 0    5 5.5 40 8.5 40  8.51  5 10    5

SFC Method 14: Apparatus: Agilient 1260

Column Lux Cellulose-2 150 × 4.6 mm I.D., 3 μm Flow rate 2.5 mL/min Runtime 4 min. Wavelength 220 nm Column temp 40° C. Solvent A EtOH + 0.05%diethylamine Gradient Time A % 0 5 4 5

SFC Method 15: Apparatus: Agilent 1260

Column Lux Cellulose-2 150 × 4.6 mm I.D., 3 μm Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 40° C. Solvent A MeOH + 0.05%diethylamine Gradient Time A %  0 5 10 5

SFC Method 16: Apparatus: Agilent 1260

Column Lux Cellulose-2 150 × 4.6 mm I.D., 3 μm Flow rate 2.5 mL/min Runtime 10 min. Wavelength 220 nm Column temp 40° C. Solvent A EtOH + 0.05%diethylamine Gradient Time A % 0    5 5.5 40 8.5 40  8.51  5 10    5

Chiral HPLC Method 1: Apparatus: SHIMADZU LC-20AB

Column CD-PH 250 × 4.6 mm I.D., 5 um Flow rate 0.8 mL/min Run time 30min. Wavelength 280 nm Column temp 30° C. Solvent A Water + 0.069% TEASolvent B MeCN Gradient Time (min) A % B %  0 90 10 15 20 80 17 90 10 3090 10

Chiral HPLC Method 2: Apparatus: SHIMADZU LC-20AB

Column OD-RH 150 × 4.6 mm I.D., 5 um Flow rate 0.8 mL/min Run time 25min. Wavelength 220 nm Column temp 30° C. Solvent A Water + 0.07% TEASolvent B MeCN Gradient Time A % B %  0 90 10 14 20 80 15 90 10 25 90 10

General procedures for synthesis of intermediates and the compounds ofgeneral Formula I are described in reaction Scheme 1, and arespecifically illustrated in the preparations and Examples. Within thescope of the present invention are variations of the describedprocedures, which are known to a person skilled in the art.

The compounds of the invention are prepared as described in Scheme 1.Several of the compounds of general Formula I contain two chiral carbonatoms, and are formed as a mixture of diastereomers. When this is thecase, the diastereomers may be separated, to yield the singlestereoisomers Ia and Ib.

Scheme I depicts the preparation of the compounds of general Formula Iby two general routes. The first route is the synthesis of compounds ofFormula I by reaction of an enantiomerically pure amine of generalFormula II, and an acid of general Formula III, through methodology wellknown in the art for the conversion of an acid and an amine into anamide. This methodology includes the formation of reactive derivativesof the acid of Formula III, including, but not limited to, activatedesters and reactive mixed anhydrides, followed by condensation withamines of general Formula II. One such methodology is performing thecondensation in the presence of HATU((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) and a suitable base such as DIPEA(diisopropylethylamine), in a solvent such as dichloromethane.

Alternatively, when R² is H, the compounds of general Formula I can beprepared via a second general route, in which intermediates of generalformula V, are treated with a suitable reducing agent such as NaBH₄, ina suitable solvent such as methanol. The intermediates of formula V canbe obtained from enantiomerically pure amines of general Formula II, anda carboxylic acid of general Formula IV (R═H). This transformation canbe effected using similar reaction conditions as described above for thecondensation of II and III to form I.

A variation of this procedure is the direct coupling reaction between achiral amine of general Formula II and a carboxylic acid ester ofgeneral Formula IV (R=Me, Et). This reaction can be performed by heatingthe reactants to reflux in a suitable solvent such as toluene, in thepresence of a suitable base such as DIPEA, and in the presence of acatalytic amount of a suitable catalyst such as DMAP (4-dimethylaminopyridine).

The optically active amines of general Formula II can be prepared asoutlined in Scheme 2:

Aldehydes of general formula VI can be condensed with(R)-2-methylpropane-2-sulfinamide in a suitable solvent such asdichloroethane, in the presence of a drying agent, such astitanium(IV)isopropoxide, or cupric sulfate. The formed sulfinyl imineis treated with R³MgBr in a suitable inert solvent such as THF, to yieldthe corresponding substituted(R)-2-methyl-N—((S)-1-aryl-alkyl)propane-2-sulfinamides VII, which areconverted to the compounds of general Formula II by treatment with anappropriate acid in an appropriate solvent, such as HCl in MeOH.

The aldehydes of formula VI, used to prepare the compounds of theinvention, are commercially available, or may be prepared as describedin the literature, see fx. Journal of Medicinal Chemistry, 45(18),3891-3904; 2002.

In a variation of this procedure, the chiral amines of Formula II can beobtained from an aryl ketone, through hydride reduction of theintermediate sulfinyl imine with a reagent such as L-Selectride; asshown in Scheme 3.

The ketones used to prepare the compounds of the invention, arecommercially available, or may be prepared by methods known to theperson skilled in the art.

Another variation of this procedure, particularly suited for accessingchiral amines of general Formula II, in which R³ is a hydroxymethylenederivative, is outlined in Scheme 4.

In this procedure, glyoxylate sulfinyl imine, formed in a condensationreaction between a glyoxylic ester and(R)-2-methylpropane-2-sulfinamide, can be reacted with a suitablysubstituted boronic acid using a suitable catalyst such asbis(acetonitrile) (1,5-cyclooctadiene)rhodium(I) tetra-fluoroborate, ina suitable solvent such as dioxane, as described in JP 2017/095366A. Theresulting intermediates VIII can be hydrolysed and re-protected to yieldintermediates of general Formula IX, which may be further derivatised toaccess the desired R³ substituent. In the compounds of the invention,the carboxylic ester group of IX can be reduced to hydroxymethyleneusing LAH (lithium aluminium hydride), and difluoromethylated using asuitable reagent such as 2,2-difluoro-2-(fluorosulfonyl) acetic acidunder conditions such as CuI catalysis, in a suitable solvent such asacetonitrile. The skilled artisan will recognise that othertransformations are possible from intermediates of general Formula IX;the present invention is intended to include such alternativetransformations.

The carboxylic acids of general Formula III can be prepared as outlinedin Scheme 5:

Ketones of general formula X are reacted with an alkyl ester ofbromoacetic acid activated with for example Zn and iodine, to yield thecorresponding aldol adduct. In an alternative procedure, the bromoaceticacid ester can be activated using Zn and TMSCl (trimethylsilylchloride).In a final step, hydrolysis of the alkyl ester is accomplished bytreatment with an appropriate base such as NaOH or LiOH in anappropriate solvent, such as water, or an alcohol in water, and followedby acidification with an appropriate acid to yield the compounds ofFormula III.

Preparation of Intermediates IIa: (S)-1-(3-(Trifluoromethoxy)phenyl)ethanamine hydrochloride

Step 1: Preparation of (R)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide

A mixture of 3-(trifluoromethoxy)benzaldehyde (24.8 g, 130.4 mmol),(R)-2-methylpropane-2-sulfinamide (19 g, 156.5 mmol) and CuSO₄ (31.2 g,195.7 mmol) in DCE (1,2-dichloroethane) (500 mL) was stirred at 55° C.for 24 hours. The mixture was filtered and the filter cake was washedwith DCM (dichloromethane) (200 mL). The organic phases were combinedand concentrated. The residue was purified by flash silica gelchromatography with an eluent of 0˜15% ethyl acetate/petroleum ether(gradient) to yield the product (33 g, 86% yield).

¹H NMR (CDCl₃ 400 MHz): δ 8.59 (s, 1H), 7.79-7.71 (m, 2H), 7.53 (t,J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 1.28 (s, 9H).

Step 2: Preparation of(R)-2-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide

To a solution of(R)-2-methyl-N-[[3-(trifluoromethoxy)phenyl]methylene]propane-2-sulfinamide(17.6 g, 59.8 mmol) in DCM (250 mL) was added MeMgBr (3M in Et₂O, 40 mL)dropwise at 0° C. The resulting mixture was stirred at 0° C. for 1 hourand 15° C. for 16 hours. The mixture was cooled to 0° C., and sat. NH₄Clsolution was added. The resulting mixture was extracted with DCM (100mL×2). The organic phases were washed with brine (200 mL), dried overNa₂SO₄ and concentrated. The residue was purified by flash silica gelchromatography with an eluent of 0˜50% ethyl acetate/petroleum ether(gradient) to give the product (10.3 g, 56% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.37 (t, J=8.0 Hz, 1H), 7.27-7.24 (m, 1H),7.21 (s, 1H), 7.13 (br d, J=8.0 Hz, 1H), 4.65-7.59 (m, 1H), 3.32 (br d,J=2.4 Hz, 1H), 1.54 (d, J=6.4 Hz, 3H), 1.22 (s, 9H).

Step 3: Preparation of (S)-1-(3-(trifluoromethoxy)phenyl)ethan aminehydrochloride

(R)-2-methyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]propane-2-sulfinamide(10 g, 32.3 mmol) in MeOH (75 mL) was treated with HCl/MeOH (75 mL) andstirred at 15° C. for 16 hours. The mixture was concentrated to give(S)-1-(3-(trifluoromethoxy)phenyl)ethanamine hydrochloride (9 g, crude)which was used directly without further purification.

IIb: (1S)-1-[3-(2,2,2-Trifluoroethoxy)phenyl]ethanamine hydrochloride

Step 1: Preparation of 3-(2,2,2-trifluoroethoxy)benzaldehyde

A mixture of 3-hydroxybenzaldehyde (5 g, 40.9 mmol),2,2,2-trifluoroethyl trifluoromethanesulfonate (10.5 g, 45 mmol) andCs₂CO₃ (26.7 g, 81.9 mmol) in DMF (60 mL) was stirred at 20° C. for 2hours. The mixture was filtered and the filter cake was washed withethyl acetate (200 ml). The filtrate was washed with water (100 mL×2)and brine (100 mL×2), dried over Na₂SO₄ and concentrated. The crude waspurified by column chromatograph on silica gel (20% ethyl acetate inpetroleum ether) to give the product (8.0 g, 95% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.58-7.51 (m, 2H), 7.42 (s, 1H), 7.27-7.25 (m,1H), 4.42 (q, J=12.0 Hz, J=8.0 Hz, 2H).

Step 2: Preparation of(R)-2-methyl-N-[[3-(2,2,2-trifluoro-ethoxy)phenyl]methylene]propane-2-sulfinamide

A mixture of 3-(2,2,2-trifluoroethoxy)benzaldehyde (8.0 g, 39.2 mmol),(R)-2-methylpropane-2-sulfinamide (5.2 g, 43.1 mmol) and CuSO₄ (9.4 g,58.8 mmol) in DCE (70 mL) was stirred at 55° C. for 20 hours. Themixture was filtered and the filter cake was washed with DCM (100 mL).The organic phases were concentrated and purified by columnchromatograph on silica gel (11% ethyl acetate in petroleum ether) toyield the product (10.0 g, 83% yield).

¹H NMR (CDCl₃ 400 MHz): δ 8.55 (s, 1H), 7.50-7.42 (m, 3H), 7.13 (d,J=5.2 Hz, 1H), 4.41 (q, J=12.0 Hz, J=8.0 Hz, 2H), 1.27 (s, 9H).

Step 3: Preparation of (R)-2-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide

To a solution of(R)-2-methyl-N-[[3-(2,2,2-trifluoroethoxy)phenyl]methylene]propane-2-sulfinamide(10 g, 32.5 mmol) in DCM (100 mL) at 0° C. was added MeMgBr (3M, 43 mL)dropwise. The resulting mixture was stirred at 0° C. for 1 hour and 20°C. for 3 hours. The mixture was cooled to 0° C., and sat. NH₄Cl solutionwas added. The resulting mixture was extracted with DCM (100 mL×2). Theorganic phases were washed with brine (200 mL), dried over Na₂SO₄ andconcentrated. The crude was purified by column chromatograph on silicagel (petroleum ether:ethyl acetate=1:1) to give the product (9 g, 79%yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.27 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz,1H), 6.93 (d, J=2.4 Hz, 1H), 6.83 (dd, J=8.4 Hz, J=2.4 Hz, 1H),4.56-4.54 (m, 1H), 4.34 (dd, J=16.4 Hz, J=8.4 Hz, 1H), 3.30 (br s, 1H),1.51 (d, J=8.4 Hz, 3H), 1.20 (s, 9H). NH is not observed.

Step 4: Preparation of(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethanamine hydrochloride

To a solution of(R)-2-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]propane-2-sulfinamide(9 g, 27.8 mmol) in MeOH (100 mL) was added HCl/MeOH (80 mL, 4M). Theresulting mixture was stirred at 20° C. for 4 hours, and wasconcentrated to give the crude product (8 g), which was used directlywithout further purification.

IIc: (S)-1-(3-(Difluoromethoxy)phenyl) ethan-1-amine hydrochloride

Step 1: Preparation of(R)—N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

To a mixture of 3-(difluoromethoxy)benzaldehyde (2 g, 11.6 mmol) and2-methylpropane-2-sulfinamide (1.7 g, 13.9 mmol) in DCE (60 mL) wasadded CuSO₄ (9.3 g, 58.1 mmol) at 55° C. under N2. The mixture wasstirred at 55° C. for 12 hours, filtered and the filtrated wasconcentrated. The crude product was purified by silica gel column elutedwith petroleum ether/Ethyl acetate=20:1-10:1 to give(R)—N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide(2.5 g, 70% yield).

Step 2: Preparation of (R)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R)—N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2g, 7.3 mmol) in DCM (30 mL) was added bromo(methyl)magnesium (3M inEt₂O, 4.8 mL) dropwise at 0° C. The resulting mixture was stirred at 0°C. for 1 hour and 20° C. for 16 hours. The reaction was quenched withNH₄Cl (sat. aq, 10 mL), and aqueous phase was extracted with ethylacetate (30 mL×3). The combined organic phase was washed with brine (40mL×2), dried with anhydrous Na₂SO₄, filtered, concentrated and purifiedby silica gel chromatography (petroleum ether/Ethyl acetate=5:1-1:1) toafford (R)—N—((S)-1-(3-(difluoromethoxy)phenyl))-2-methylpropane-2-sulfinamide (960 mg, 45.4% yield).

Step 3: Preparation of (S)-1-(3-(difluoromethoxy)phenyl)ethan aminehydrochloride

To a solution of(R)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide(0.8 g, 2.8 mmol) in MeOH (4 mL) was added HCl/MeOH (4M, 2 mL). Theresulting mixture was stirred at 25° C. for 3 hours, and the reactionwas concentrated to afford (S)-1-(3-(difluoromethoxy)phenyl)ethan aminein 1.6 g crude yield, which was used directly without furtherpurification.

IId: (S)-1-(3-(Trifluoromethyl)phenyl) ethan-1-amine hydrochloride

Step 1: Preparation of (R)-2-methyl-N-(3-(trifluoromethyl)benzylidene)propane-2-sulfinamide

A mixture of 3-(trifluoromethyl)benzaldehyde (4.5 g, 25.8 mmol),(R)-2-methylpropane-2-sulfinamide (3.8 g, 31 mmol) and CuSO₄ (6.2 g,38.8 mmol) in DCE (20 mL) was stirred at 55° C. for 24 hours. Themixture was filtered and filter was washed with DCM (100 mL). Thefiltrate was concentrated, and the residue was purified by columnchromatography (SiO₂, petroleum ether/Ethyl acetate) to afford theproduct in 4.6 g yield (58%).

¹H NMR (CDCl₃, 400 MHz): δ 8.60 (s, 1H), 8.09 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 1.25 (s, 9H).

Step 2: Preparation of(R)-2-methyl-N—((S)-1-(3-trifluoro-methyl)phenyl)ethyl)propane-2-sulfinamide

To a solution of(R)-2-methyl-N-(3-(trifluoromethyl)benzyli-dene)propane-2-sulfinamide (2g, 7.2 mmol) in DCM (50 mL) at 0° C. MeMgBr (3M in Et₂O, 9.6 mL) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1 hourand 25° C. for 3 hours. The reaction mixture was cooled to 0° C., andsat. aa. NH₄Cl solution was added. The mixture was extracted with DCM(50 mL×3). The combined organic phases were washed with brine (50 mL×2),dried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography (SiO₂, petroleum ether/Ethyl acetate) to afford thedesired product (1.3 g, 61% yield).

¹H NMR (CDCl₃, 400 MHz): δ 7.40-7.65 (4H), 4.11-4.06 (m, 1H), 1.51 (d,J=6.8 Hz, 3H), 1.17 (s, 9H). NH not observed.

Step 3: Preparation of (S)-1-[3-(trifluoromethyl)phenyl]ethan aminehydrochloride

To a solution of (R)-2-methyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfonamide (1.3 g, 4.4 mmol) in MeOH (20 mL) wasadded HCl/MeOH (4M, 20 mL). The resulting mixture was stirred at 25° C.for 20 hours, and then concentrated to afford the product in 850 mgyield. The crude was used directly without further purification.

IIe: (S)-1-(3-(trifluoromethoxy)phenyl) propan-1-amine hydrochloride

Step 1: Preparation of (R)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide

A mixture of 3-(trifluoromethoxy)benzaldehyde (10.0 g, 52.60 mmol),(R)-2-methylpropane-2-sulfinamide (7.7 g, 63.1 mmol) and CuSO4 (12.6 g,78.9 mmol) in DCE (200 mL) was stirred at 55° C. for 16 hours. Themixture was filtered and the filter cake was washed with DCM (200 mL).The filtrate was concentrated. The residue was purified by flashchromatography on silica gel (Eluent of 0˜10% Ethylacetate/petroleumether gradient) to give(R)-2-methyl-N-[[3-(trifluoromethoxy)phenyl]methylene]propane-2-sulfinamidein a yield of 12.6 g, (81.7%).

Step 2: Preparation of(R)-2-methyl-N—((S)-1-(3-(trifluoro-methoxy)phenyl)propyl)propane-2-sulfinamide

To a solution of (R)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (2.0 g, 6.8 mmol) in DCM (40 mL) at 0°C. EtMgBr (3M in Et₂O, 9.1 mL) was added drop-wise. The resultingmixture was stirred at 0° C. for 1 hour and 20° C. for 3 hours. Themixture was cooled to 0° C. and sat.aq NH₄Cl (100 mL) was added. Themixture was extracted with DCM (100 mL×2), the phases were separated,and the organic layer was washed with brine (200 mL), dried over Na₂SO₄and concentrated. The residue was purified by flash silica gelchromatography (Eluent of 0˜50% Ethyl acetate/petroleum ether gradient)to yield the product (1.4 g, 62% yield).

Step 3: Preparation of (S)-1-[3-(trifluoromethoxy)phenyl]propan-1-aminehydrochloride

To a solution of(R)-2-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide (1.4 g, 4.2 mmol) in MeOH (40 mL) was added HCl/MeOH (4M, 20 mL).The resulting mixture was stirred at 30° C. for 12 hours and thenconcentrated to yield the crude(S)-1-[3-(trifluoromethoxy)phenyl]propan-1-amine hydrochloride, whichwas used without further purification (1 g)

IIf: (R)-2-Methoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine

Step 1: Preparation of 2-methoxy-1-(3-(trifluoromethoxy)phenyl) ethanone

To a solution of 2-bromo-1-(3-(trifluoromethoxy)phenyl) ethanone (3.5 g,12.4 mmol) in MeOH (60 mL) was added Ag₂CO₃ (3.8 g, 13.6 mmol) andBF₃.Et₂O (2.1 g, 14.8 mmol). The mixture was stirred at 50° C. for 16hours under N₂. The reaction mixture was filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, eluent of 0˜5%Ethyl acetate/petroleum ether) to give2-methoxy-1-(3-(trifluoro-methoxy)phenyl)ethanone (2.1 g, 64% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.52 (t,J=8.4 Hz, 1H), 7.46-7.42 (m, 1H), 4.68 (s, 2H), 3.51 (s, 3H).

Step 2: Preparation of(R)—N-(2-methoxy-1-(3-(trifluoro-methoxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

To a solution of 2-methoxy-1-(3-(trifluoromethoxy)phenyl) ethanone (500mg, 2.1 mmol) in THE (15 mL) was added titanium(IV)isopropoxide (910 mg,3.2 mmol) and (R)-2-methylpropane-2-sulfinamide (336 mg, 2.8 mmol). Themixture was stirred at 50° C. for 1 hour under N₂. The reaction mixturewas quenched with brine (40 mL) and extracted with ethyl acetate (30mL×2). The combined organic phases were dried over MgSO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,eluent of 0˜10% Ethyl acetate/petroleum ether) to give(R)—N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (160 mg, 20% yield).

Step 3: Preparation of(R)—N—((R)-2-methoxy-1-(3-(trifluoro-methoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R)—N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide(160 mg, 0.5 mmol) in THE (5 mL) was added L-selectride (1M in THF, 1.42mmol, 1.42 mL) at 0° C. The mixture was stirred at 20° C. for 16 hours.The reaction mixture was diluted with methanol (20 mL), and thenfiltered and concentrated. The residue was purified by columnchromatography (SiO₂, eluent of 0˜10% Ethyl acetate/petroleum ether) togive the desired product (100 mg, 59% yield).

¹H NMR (400 MHz, DMSO-d⁶) δ 7.46-7.40 (m, 3H), 7.27-7.25 (m, 1H), 5.86(d, J=8.8 Hz, 1H), 5.25 (d, J=5.6 Hz, 2H), 4.84-4.72 (m, 1H), 3.25 (s,3H), 1.09 (s, 9H).

Step 4: Preparation of (R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethanamine

(R)—N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide(280 mg, 0.8 mmol) in HCl/MeOH (10 mL, 4M) was stirred at 20° C. for 14hours. The reaction mixture was concentrated, and the residue dilutedwith water (30 mL), added ammonium hydroxide to pH=8˜9 and extractedwith ethyl acetate (30 mL×2). The combined organic extracts were driedover MgSO₄, filtered and concentrated to give the product as a yellowoil (170 mg, 88% yield). The product was used directly without furtherpurification.

IIg: (1R)-2-(Difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine

Step 1: Preparation of ethyl 2-[(R)-tert-butylsulfinyl]imino acetate

To a solution of ethyl 2-oxoacetate (7.5 g, 36.7 mmol) and(R)-2-methylpropane-2-sulfinamide (4.9 g, 40.4 mmol) in DCM (150 mL) wasadded CuSO₄ (12.9 g, 80.8 mmol), and the reaction mixture was stirred at25° C. for 24 hours. The solid was filtered off, washed with ethylacetate (50 mL) and the organic phases were combined and concentrated.The resulting residue was purified by column chromatography (silica gel,petroleum ether/ethyl acetate, 5/1) to yield the desired product (5.1 g,67.6% yield).

Step 2: Preparation of ethyl(2R)-2-[[(R)-tert-butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate

To a solution of ethyl-2-[(R)-tert-butylsulfinyl]iminoacetate (7 g, 34.1mmol) and [3-(trifluoromethoxy)phenyl]boronic acid (8.4 g, 40.9 mmol) indioxane (100 mL) was added [Rh(COD) (MeCN)₂]BF₄ (1.3 g, 3.4 mmol) andthis mixture was stirred at 80° C. for 16 hours. The product waspurified by silica gel chromatography (petroleum ether:ethylacetate=5:1) to yield 9.8 g (78%).

Step 3: Preparation of ethyl(2R)-2-amino-2-[3-(trifluoro-methoxy)phenyl]acetate hydrochloride

To a solution of ethyl(2R)-2-[[(R)-tert-butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate (9.8 g, 26.7 mmol) in MeOH (100 mL), was added HCl/MeOH (4 M,100 mL) and this mixture was stirred at 25° C. for 2 hours, and thenconcentrated to afford ethyl(2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]acetate (7.8 g, crude).

Step 4: Preparation of ethyl(2R)-2-(tert-butoxycarbonylamino)-2-[3-(trifluoromethoxy)phenyl] acetate

To a mixture of ethyl (2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]acetatehydrochloride (6 g, 20 mmol) in THE (150 mL), was added Boc₂O (8.7 g, 40mmol). Then NaHCO₃ (1.7 g, 20 mmol) was added to this solution andstirred at 25° C. for 16 hours. This mixture was concentrated andpurified by chromatography on silica (petroleum ether:ethylacetate=10:1) to afford the product (7.2 g, 99% yield).

Step 5: Preparation of tert-butylN-[(1R)-2-hydroxy-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate

To a suspension of LiAlH₄ (1.7 g, 44 mmol) in THE (200 mL) was addedethyl(2R)-2-(tert-butoxycarbonylamino)-2-[3-(trifluoro-methoxy)phenyl]acetate(4 g, 11 mmol) in THE (25 mL), with ice-cooling. Following addition, thereaction was allowed to warm to 25° C. and was stirred for 2 hours.Anhydrous magnesium sulfate was added and then one drop of water andethyl acetate were successively added. Insoluble substances werefiltered off through a pad of celite. The filtrate was concentrated andpurified by chromatography on silica (SiO₂; petroleum ether:ethylacetate=5:1) (2.1 g, 59% yield).

Step 6: Preparation of tert-butylN-[(1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate

To a solution of tert-butylN-[(1R)-2-hydroxy-1-[3-(trifluoro-methoxy)phenyl]ethyl] carbamate (1.5g, 4.7 mmol) in MeCN (20 mL), CuI (360 mg, 1.9 mmol) was added andstirred at 25° C. under N₂ atmosphere for 30 minutes. Subsequently, asolution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (1.7 g, 9.3 mmol)in MeCN (5 mL) was added at 45° C. over 30 minutes, and the reaction wasstirred at 45° C. for 1 hour. This mixture was concentrated and thendiluted by ethyl acetate (100 mL), filtered and concentrated to affordthe desired product (1.5 g, crude).

Step 7: Preparation of(1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine

To a solution of tert-butylN-[(1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate(1.5 g, 4 mmol) in MeOH (15 mL), was added HCl/MeOH (4M in MeOH, 30 mL)at 25° C., and the reaction was stirred at 25° C. for 30 minutes.Ammonium hydroxide (30%) was added to pH-9, and this solution wasconcentrated and purified by chromatography on silica (SiO₂; petroleumether:ethyl acetate=2:1) to afford(1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine (700mg, 64% yield).

IIIa: 2-(1-Hydroxycyclobutyl)acetic acid

Step 1: Preparation of ethyl 2-(1-hydroxycyclobutyl)acetate

Zn (14.9 g, 228.3 mmol) in THE (20 mL) was added TMSCl (1.9 g, 17.1mmol) in portions. The resulting mixture was stirred at 20° C. for 15min and then refluxed. The reaction mixture was cooled to roomtemperature, and ethyl 2-bromoacetate (28.6 g, 171.2 mmol) was addeddropwise at such a rate that the reaction boiled gently. The resultingmixture was stirred at 70° C. for 1 hour and then at 20° C. for 1 hour,then a solution of cyclobutanone (10 g, 142.7 mmol) in THE (5 mL) wasadded. The mixture was stirred at 20° C. for another 2 hours. Themixture was poured into NH₃.H₂O (150 mL, 25%) on ice and extracted withethyl acetate (100 mL×2). The organic layer was washed with water (200mL×2) and brine (100 ml×2), dried over Na₂SO₄ and concentrated to givethe product (12 g, crude).

¹H NMR (CDCl₃ 400 MHz): δ 4.20-4.14 (m, 2H), 3.69 (s, 1H), 2.65 (s, 2H),2.17-2.12 (m, 2H), 2.03-2.00 (m, 2H), 1.78 (m, 1H), 1.58 (m, 1H), 1.27(t, J=7.6 Hz, 3H).

Step 2: Preparations of 2-(1-hydroxycyclobutyl)acetic acid

NaOH (6.3 g, 158.05 mmol) was dissolved in MeOH (150 mL) and H₂O (50mL), and ethyl 2-(1-hydroxycyclobutyl)acetate (10 g, 63.2 mmol) wasadded. The mixture was stirred at 20° C. for 16 hours and thenconcentrated, and the residue was acidified by 2N HCl solution to pH=2-3and extracted with ethyl acetate (200 ml×2). The organic extract waswashed with water (100 mL×2) and brine (100 mL×2), dried over Na₂SO₄ andconcentrated to give the crude product (6 g, crude).

¹H NMR (CDCl₃ 400 MHz): δ 2.74 (s, 2H), 2.23-2.05 (m, 4H), 1.81 (m, 1H),1.63-1.58 (m, 1H).

IIIb: 2-(3,3-Difluoro-1-hydroxycyclobutyl)acetic acid

Step 1: Preparation of ethyl2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate

To a solution of 3,3-difluorocyclobutanone (0.2 g, 1.9 mmol), Zn (198mg, 3 mmol) and I₂ (10 mg, 0.04 mmol) in THE (13 mL) under N₂, ethyl2-bromoacetate (378 mg, 2.3 mmol) was added dropwise. The mixture wasstirred at 55° C. for 6 hours. H₂SO₄ (10%, 10 mL) was carefully added tothe reaction mixture at 0° C., and the mixture was extracted with ethylacetate (20 mL×3). The organic extract was washed with NaHCO₃ (sat.aq,10 mL), dried over Na₂SO₄ and concentrated. The crude product (0.26 g)was used directly without further purification.

Step 2: Preparation of 2-(3,3-difluoro-1-hydroxy-cyclobutyl) acetic acid

To a solution of ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl) acetate(0.26 g, 1.3 mmol) in MeOH (10 mL) and H₂O (2 mL), NaOH (107 mg, 2.7mmol) was added at 0° C. The mixture was stirred at 20° C. for 8 hours.The reaction solution was cooled to 0° C. and 1N HCl was added to thesolution until pH reached 1-2. The residue was diluted with brine (10mL) and extracted with methyl-tert-butyl ether (30 mL×5). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated. Thecrude product (0.24 g) was used without further purification.

IIIc: 3-Hydroxy-4-methyl-3-(trifluoromethyl)pentanoic acid

Step 1: Preparation of ethyl3-hydroxy-4-methyl-3-(trifluoro-methyl)pentanoate

To a mixture of Zn (560 mg, 8.6 mmol), I₂ (7 mg, 0.03 mmol) in THE (5mL) was added ethyl 2-bromoacetate (524 mg, 3.1 mmol) and1,1,1-trifluoro-3-methyl-butan-2-one (0.4 g, 2.9 mmol) at 15° C. Themixture was stirred at 60° C. for 6 hours. H₂SO₄ (10% aq, 4 mL) wasadded, and the mixture was extracted with ethyl acetate (10 mL×4). Thecombined organic phases were washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated to give ethyl3-hydroxy-4-methyl-3-(trifluoromethyl)pentanoate (1 g, crude)

Step 2: Preparation of 3-hydroxy-4-methyl-3-(trifluoromethyl) pentanoicacid

A mixture of ethyl 3-hydroxy-4-methyl-3-(trifluoro-methyl)pentanoate(1.5 g, crude) and LiOH.H₂O (552 mg, 13.2 mmol) in THE (20 mL) and H₂O(10 mL) was stirred at 15° C. for 16 hours. The pH was adjusted to ˜3with 2M HCl, and the mixture extracted with ethyl acetate (5 mL×4). Thecombined organic extract was washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated to give3-hydroxy-4-methyl-3-(trifluoromethyl)pentanoic acid (1.1 g, crude) as ayellow solid, which was used directly in the next step without furtherpurification.

IIId: 4,4,5,5-Tetrafluoro-3-hydroxy-3-methylpentanoic acid

Step 1: Preparation of ethyl4,4,5,5-tetrafluoro-3-hydroxy-3-methylpentanoate

To a solution 3,3,4,4-tetrafluorobutan-2-one (2.00 g, 13.88 mmol), Zn(1.0 g, 15.7 mmol) and I₂ (35.2 mg, 0.14 mmol) in THE (20 mL), ethyl2-bromoacetate (2.4 g, 14.3 mmol) was added dropwise under N₂ at 20° C.The mixture was stirred at 60° C. for 6 hours. The reaction mixture wascooled to 0° C., and H₂SO₄ (15 ml, 10% aq.) was carefully added. Themixture was extracted with ethyl acetate (80 mL×3), and the combinedorganic extract was washed with sat.aq NaHCO₃ (30 mL), dried over Na₂SO₄and concentrated. The title compound (2.5 g, crude) was obtained andused in the next step without further purification.

Step 2: Preparation of 4,4,5,5-tetrafluoro-3-hydroxy-3-methylpentanoicacid

To a solution of ethyl 4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-pentanoate(2.5 g, 10.8 mmol) in MeOH (80 mL) and H₂O (25 mL), NaOH (1.1 g, 26.9mmol) was added at 0° C. The mixture was stirred at 20° C. for 8 hoursand concentrated. The aqueous layer was acidified with 1N HCl aq. topH=1-2, and extracted with methyl-tert-butyl ether (30 mL×5). Thecombined organic extract was dried over Na₂SO₄, and concentrated. Thetitle compound was obtained (2.10 g, crude) and used without furtherpurification.

IIIe: 5,5,5-Trifluoro-3-hydroxy-3-methylpentanoic acid

Step 1: Preparation of ethyl5,5,5-trifluoro-3-hydroxy-3-methylpentanoate

To a mixture of Zn (6.9 g, 104.7 mmol) and I₂ (89 mg, 0.35 mmol) in THE(80 mL) was added 4,4,4-trifluorobutan-2-one (4.4 g, 34.9 mmol) andethyl 2-bromoacetate (6.4 g, 38.4 mmol) at 15° C. The mixture wasstirred at 60° C. for 6 hours. The reaction mixture was cooled to 0° C.and quenched with H₂SO₄ (100 mL, 10% aq). The mixture was extracted withethyl acetate (15 mL×3). The combined organic extract was washed withbrine (15 mL) and dried over Na₂SO₄, filtered and concentrated. Theproduct was obtained (11.00 g, crude) and was used directly withoutfurther purification.

Step 2: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid

A mixture of ethyl 5,5,5-trifluoro-3-hydroxy-3-methyl-pentanoate (11 g,crude) and NaOH (4.1 g, 102.7 mmol) in H₂O (150 mL) was stirred at 15°C. for 16 hours. The pH was adjusted to ˜2 with sat. KHSO₄ at 0° C., andthe mixture extracted with ethyl acetate (200 mL×3). The combinedorganic extract was washed with brine (300 mL), dried over Na₂SO₄,filtered and concentrated to afford the product (10 g, crude)

IIIf: 3-(1-Fluorocyclopropyl)-3-hydroxybutanoic acid

Step 1: Preparation of ethyl 3-(1-fluorocyclopropyl)-3-hydroxy butanoate

To a mixture of 1-(1-fluorocyclopropyl)ethanone (0.8 g, 7.8 mmol), Zn(1.5 g, 23.5 mmol) and I₂ (20 mg, 0.8 mmol) in THE (15 mL) was addedethyl 2-bromoacetate (1.4 g, 8.6 mmol) dropwise at 15° C. The mixturewas stirred at 65° C. for 6 hours. The reaction mixture was cooled to 0°C., and H₂SO₄ (10% aq, 10 mL) was added dropwise. The mixture was addedwater (30 mL) and was extracted with ethyl acetate (20 mL×3). Thecombined organic extract was washed with brine (30 mL), dried overNa₂SO₄, filtered and concentrated. The obtained product was used withoutfurther purification. Yield: 1.6 g, crude.

Step 2: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxy butanoic acid

A mixture of ethyl 3-(1-fluorocyclopropyl)-3-hydroxy-butanoate (1.6 g,crude) and NaOH (670 mg, 16.8 mmol) in H₂O (30 mL) was stirred at 15° C.for 16 hours. The pH was adjusted with 10% HCl (aq) to ˜2. The mixturewas extracted with ethyl acetate (20 mL×4), and the combined organicextract was washed with brine (40 mL), dried over Na₂SO₄, filtered andconcentrated to yield the crude product, which was used directly withoutfurther purification. (1.50 g, crude.

IIIg: 3-Cyclopropyl-3-hydroxybutanoic acid

Step 1: Preparation of yl 3-cyclopropyl-3-hydroxybutanoate

Zn (12.4 g, 190.2 mmol) in THE (150 mL) was added TMSCl (1.3 g, 11.9mmol), and the resulting mixture was stirred at 20° C. for 15 minutesand then heated to 70° C. The heating was stopped, and methyl2-bromoacetate (21.8 g, 142.7 mmol) was added in dropwise at such a ratethat the ether boiled gently. The resulting mixture was stirred at 70°C. for 1 hour and 20° C. for 1 hour, and then a solution of1-cyclopropylethanone (10 g, 118.9 mmol) in THE (50 mL) was added. Thereaction was stirred at 20° C. for 16 hours. The mixture was poured ontoNH₃—H₂O on ice (100 mL, 28%), and extracted with ethyl acetate (150mL×2). The organic extract was washed with water (150 mL) and brine (150mL), dried over Na₂SO₄ and concentrated to give the desired product (8.9g, crude).

Step 2: Preparation of 3-cyclopropyl-3-hydroxybutanoic acid

A mixture of crude methyl 3-cyclopropyl-3-hydroxybutanoate (8.9 g, 56.3mmol) and LiOH—H₂O (11.8 g, 281.3 mmol) in THE (100 mL) and H₂O (50 mL)was stirred at 20° C. for 16 hours. H₂O (50 ml) was added and extractedwith ethyl acetate (100 mL×2). The organic extracts were discarded. ThepH of the aqueous layer was adjusted to ˜5 with 2N HCl, extracted withethyl acetate (100 mL×3) and the combined organic fractions were washedwith brine (100 mL×10), dried over Na₂SO₄, filtered and concentrated togive the desired product in 30% overall yield (5.1 g)

¹H NMR (400 MHz, CDCl₃) δ 2.67-2.51 (m, 2H), 1.25 (s, 3H), 0.90-1.00 (m,1H), 0.33-0.50 (m, 4H).

IVa: Ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propanoate

Step 1: Preparation of ethyl3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propanoate

Et₃N (2.34 g, 23.5 mmol) and MgCl₂ (1.8 g, 18.4 mmol) was added to asuspension of (3-ethoxy-3-oxo-propanoyl)oxy potassium salt (2.6 g, 15.4mmol) in MeCN (30 mL) and stirred at 20° C. for 2 hours. A pre-stirredmixture of CDI (carbonyl-diimidazole) (1.4 g, 8.8 mmol) and1-(difluoromethyl) cyclopropane carboxylic acid (1 g, 7.4 mmol) in MeCN(20 mL) was added at 0° C. and stirred at 20° C. for 14 hours. Thereaction mixture was diluted with H₂O (30 mL) and extracted with ethylacetate (80 mL×2). The combined organic extracts were washed with brine(30 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (Eluent of 0˜10% Ethylacetate/petroleum ether gradient). The product was obtained in 0.98 g(65%) yield.

IVb: Ethyl 3-oxo-3-[1-(trifluoromethyl) cyclopropyl]propanoate

Step 1: Preparation of ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoate

Et₃N (6.3 g, 62.3 mmol) and MgCl₂ (4.6 g, 48.7 mmol) was added to asuspension of potassium 3-ethoxy-3-oxo-propanoate (6.9 g, 40.5 mmol) inCH₃CN (25 mL) and stirred at 20° C. for 2 hours. A pre-stirred mixtureof carbonyl diimidazole (CDI) (3.8 g, 23.3 mmol) and1-(trifluoromethyl)cyclopropane carboxylic acid (3 g, 19.5 mmol) inCH₃CN (25 mL) was added at 0° C. and stirred at 20° C. for 14 hours. Themixture was poured into water (20 mL). The aqueous phase was extractedwith ethyl acetate (30 mL×3). The combined organic phase was washed withbrine (40 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography on silica gel(petroleum ether/Ethyl acetate=30:1-10:1) to afford the product in 3.5 g(80%) yield.

Va:4,4-dimethyl-3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentaneamide

A solution of (1S)-1-[3-(trifluoromethoxy)phenyl]ethan aminehydrochloride (IIa) (5 g, 20.69 mmol), 4,4-dimethyl-3-oxo-pentanoic acid(3.28 g, 22.76 mmol), HATU (9.44 g, 24.83 mmol) and DIPEA (8 g, 62.1mmol) in DCM (250 mL) was stirred at 25° C. for 16 hours. The resultingmixture was washed with water (500 mL) and extracted with DCM (500mL×2). The organic layer was washed with brine (350 mL×2), dried overNa₂SO₄ and concentrated. The residue was purified by chromatography(SiO₂, petroleum ether/Ethyl acetate=1:0 to 3:1) to afford4,4-dimethyl-3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide(11.2 g, crude).

The following intermediates were prepared by similar methodology as Va,using the relevant intermediates

Vb:4,4-Dimethyl-3-oxo-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]pentanamide

Prepared from IIb (2.6 g, 10.1 mmol) and 4,4-dimethyl-3-oxo-pentanoicacid (1.6 g, 11.1 mmol).

Yield: 2.6 g (75%).

Vc: (S)—N-(1-(3-(Difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide

Prepared from IIc (0.8 g, 4.3 mmol) and 4,4-dimethyl-3-oxo-pentanoicacid (616 mg, 4.3 mmol)

Yield: 1.3 g crude

Vd: (S)-4,4-Dimethyl-3-oxo-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

Prepared from IId (850 mg, 3.77 mmol) and 4,4-dimethyl-3-oxo-pentanoicacid (597 mg, 4.14 mmol).

Yield: 1.12 g (94%)

Ve: (S)-4,4-Dimethyl-3-oxo-N-(1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

Prepared from IIe (1.04 g, 4.07 mmol) and 4,4-dimethyl-3-oxo-pentanoicacid (645 mg, 4.47 mmol).

Yield: 1.28 g (91%).

Vf: (S)-4-methyl-3-oxo-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

Prepared from IIb (2.89 g, 11.32 mmol) and 4-methyl-3-oxo-pentanoic acid(1.62 g).

Yield: 2.6 g (69%).

Vi: (S)-4-Methyl-3-oxo-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Prepared from IIa (2.7 g, 13.16 mmol) and 4-methyl-3-oxo-pentanoic acid(1.60 g)

Yield: 2.00 g (47%).

Vj:N-[(1R)-2-(Difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-3-oxo-pentanamide

Prepared from IIg (600 mg, 2.21 mmol) and 4,4-dimethyl-3-oxo-pentanoicacid (382 mg, 2.66 mmol)

Yield: 520 mg (51%).

Vk:N-[(1R)-2-Methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-3-oxo-pentanamide

Prepared from IIf (40 mg, 0.15 mmol) and 4,4-dimethyl-3-oxo-pentanoicacid (25 mg, 0.17 mmol)

Yield: 100 mg, (94%).

Vg:3-[1-(Difluoromethyl)cyclopropyl]-3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]propanamide

A mixture of IIa (557 mg, 2.30 mmol), IVa (0.95 g, 4.61 mmol), DMAP (57mg, 0.46 mmol) and Et₃N (2.33 g, 23.04 mmol) in toluene (30 mL) wasdegassed and purged with N₂ for 3 times, then the mixture was stirred at110° C. for 12 hours under N₂. The mixture was concentrated, and theresidue was purified by flash chromatography on silica gel (Eluent of0˜35% Ethyl acetate/petroleum ether gradient) to yield the desiredproduct (0.61 g, 72% yield).

The following were prepared by similar methodology as described for Vg,using the relevant intermediates

Vh:3-Oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-[1-(trifluoromethyl)cyclopropyl] propanamide

Prepared from IVb (2 g, 8.9 mmol) and IIa (915.3 mg, 4.5 mmol) Yield:1.7 g (97%).

V1:(S)-3-(3,3-Difluorocyclobutyl)-3-oxo-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

Prepared from methyl 3-(3,3-difluorocyclobutyl)-3-oxopropanoate (600 mg,3.12 mmol) and IIa (377 mg, 1.56 mmol).

Yield: 470 mg, (82%).

¹H NMR (CDCl₃, 400 MHz) δ 7.39-7.35 (m, 1H), 7.26-7.23 (m, 1H),7.15-7.11 (m, 2H), 5.16-5.08 (m, 1H), 3.44 (d, J=2.4 Hz, 2H), 2.86-2.71(m, 5H), 1.51 (d, J=7.2 Hz, 3H).

EXAMPLES Example 1a(S)-3-Hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

and Example 1b(R)-3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

Step 1: Preparation of3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

To a mixture of 4,4-dimethyl-3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide (Va) (5.6 g, 16.90 mmol) in MeOH (50mL) was added NaBH₄ (1.28 g, 33.8 mmol) in portions at 0° C. The mixturewas stirred at 0° C. for 1 hour. Water (50 mL) was added portionwise at0° C. This reaction was repeated on the same scale twice, and the crudeproducts from the three separate reactions were combined and worked upas follows: The mixture was concentrated to remove MeOH, and thenextracted with ethyl acetate (100 mL×4). The combined organic extractswere washed with brine (50 mL×3), dried over Na₂SO₄, filtered andconcentrated to afford3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide (16.5 g, crude).

Step 2: Separation of(S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide and(R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide(27 g, 83 mmol) was separated by chromatography.

Example 1a

Yield: 10.5 g

¹H NMR (CDCl₃ 400 MHz): δ 7.33 (t, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz,1H), 7.05-7.20 (2H), 6.40 (br, 1H), 5.15 (m, 1H), 3.64 (dd, J=2.0 Hz,8.4 Hz, 1H), 3.05 (br, 1H), 2.15-2.40 (m, 2H), 1.45 (d, J=7.2 Hz, 3H),0.88 (s, 9H).

LC-MS: t_(R)=2.548 min (LCMS Method 1), m/z=334.0 [M+H]⁺.

SFC: t_(R)=1.89 min (SFC Method 4), de=95%, [α]_(D) ²⁰=−71.7 (c=0.72g/100 mL, MeOH).

Example 1b

Yield: 10.5 g

¹H NMR (CDCl₃ 400 MHz): δ 7.32 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.6 Hz,1H), 7.13 (s, 1H), 7.10-7.07 (m, 1H), 6.52 (d, J=7.6 Hz, 1H), 5.13-5.06(m, 1H), 3.62 (dd, J=2.0 Hz, 8.4 Hz, 1H), 3.45-3.33 (m, 1H), 2.38-2.33(m, 1H), 2.23-2.17 (m, 1H), 1.44 (d, J=7.2 Hz, 3H), 0.88 (s, 9H). LC-MS:t_(R)=2.553 min (LCMS Method 1), m/z=334.0 [M+H]⁺.

SFC: t_(R)=1.87 min (SFC Method 5), de=100%, [α]_(D) ²⁰=42.3 (c=0.61g/100 mL, MeOH).

The following examples were prepared by similar methodology as describedfor 1a and 1b, using the relevant intermediates:

Example 2a 3-Hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

and Example 2b 3-Hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

Step 1: Preparation of3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

3-Hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamidewas prepared from Vb, in 84% yield.

Step 2: Separation of(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamideand(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]pentanamide (0.84 g, 2.52 mmol) was separated by chiralSFC.

Example 2a

Yield: 0.25 g

¹H NMR (CDCl₃, 400 MHz) δ 7.30 (t, J=7.6 Hz, 1H), 7.01 (d, J=7.6 Hz,1H), 6.93 (s, 1H), 6.85 (dd, J=8.4 Hz, 2.8 Hz, 1H), 6.08 (br d, J=5.2Hz, 1H), 5.13 (m, 1H), 4.36 (q, J=16.0 Hz, 8.0 Hz, 2H), 3.68 (dd, J=10.4Hz, 3.0 Hz, 1H), 3.24 (d, J=3.2 Hz, 1H), 2.39-2.23 (m, 2H), 1.49 (d,J=6.8 Hz, 3H), 0.93 (s, 9H)

LC-MS: t_(R)=2.68 min (LCMS Method 2), m/z=348.0 [M+H]⁺.

SFC: t_(R)=1.78 min (SFC Method 1), de=98.3%, [α]_(D) ²⁰=−68.0 (c=0.25,MeOH).

Example 2b

Yield: 0.37 g

¹H NMR (CDCl₃, 400 MHz) δ7.29 (t, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H),6.94 (s, 1H), 6.84 (dd, J=8.0, 2.4 Hz, 1H), 6.04 (m, 1H), 5.13 (m, 1H),4.36 (q, J=16.0 Hz, 8.0 Hz, 2H), 3.70-3.67 (m, 1H), 3.15 (d, J=2.8 Hz,1H), 2.40-1.96 (m, 2H), 1.50 (d, J=7.2 Hz, 3H), 0.93 (s, 9H) LC-MS:t_(R)=2.543 min (LCMS Method 2), m/z=348.0 [M+H]⁺.

SFC: t_(R)=1.87 min (SFC Method 1), de=92.0%, [α]_(D) ²⁰=−53.3 (c=0.21,MeOH).

Example 3a: N—((S)-1-(3-(Difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

and Example 3b: N—((S)-1-(3-(Difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Step1: Preparation ofN—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Prepared from Vc, 84% yield.

Step 2: Separation of(S)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamideand(R)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentan-amide

N—((S)-1-(3-(Difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide(450 mg) was separated by chiral SFC.

Example 3a

Yield: 168 mg

¹H NMR (CDCl₃ 400 MHz): δ 7.31-7.29 (m, 1H), 7.26-7.24 (m, 1H),7.16-7.14 (m, 1H), 7.10-6.98 (m, 1H), 6.49 (t, J=76 Hz, 1H), 6.14 (brs,1H), 5.14-5.07 (m, 1H), 3.66 (d, J=10.4 Hz, 1H), 3.17 (s, 1H), 2.38-2.34(m, 1H), 2.28-2.18 (m, 1H), 1.47-1.40 (m, 3H), 0.98 (s, 9H).

LC-MS: t_(R)=2.161 min (LCMS Method 3), m/z=316.1 [M+H]⁺.

SFC: t_(R)=2.15 min (SFC Method 2), de=96.6%, [α]_(D) ²⁰=−16 (c=0.25,MeOH).

Example 3b

Yield: 126 mg

¹H NMR (CDCl₃ 400 MHz): δ 7.34-7.30 (m, 1H), 7.16-7.12 (m, 1H),7.04-6.97 (m, 2H), 6.31 (t, J=76 Hz, 1H), 6.14 (brs, 1H), 5.12-5.06 (m,1H), 3.67-3.62 (m, 1H), 3.29 (s, 1H), 2.37-2.31 (m, 1H), 2.26-2.19 (m,1H), 1.47-1.43 (m, 3H), 0.98 (s, 9H).

LC-MS: t_(R)=2.16 min (LCMS Method 3), m/z=316.1 [M+H]⁺.

SFC: t_(R)=2.42 min (SFC Method 2), de=100%, [α]_(D) ²⁰=−57.6 (c=0.5,MeOH).

Example 4a: 3-Hydroxy-4,4-dimethyl-N— ((S)-1-(3-(trifluoro-methyl)phenyl)ethyl) pentanamide

and Example 4b: 3-Hydroxy-4,4-dimethyl-N— ((S)-1-(3-(trifluoro-methyl)phenyl)ethyl) pentanamide

Step 1: Preparation of3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

Prepared from Vd (980 mg, 87% yield).

Step 2: Separation of(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamideand(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

3-Hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide was separated by chromatography on silica, (petroleum ether:Ethylacetate=3:1).

Example 4a: Yield: 220 mg

¹H NMR (CDCl₃ 400 MHz): δ 7.56 (s, 1H), 7.52-7.43 (m, 3H), 6.22-6.21 (m,1H), 5.21-5.14 (m, 1H), 3.68-3.64 (m, 1H), 3.14 (d, J=3.2 Hz, 1H),2.40-2.36 (m, 1H), 2.26-2.20 (m, 1H), 1.50 (d, J=7.2 Hz, 3H), 0.91 (s,9H).

LC-MS: t_(R)=2.48 min (LCMS Method 1), m/z=318.0 [M+H]⁺.

SFC: t_(R)=1.56 min (SFC Method 3), de=100%, [α]_(D) ²⁰=−25.5 (c=0.19g/100 mL, MeOH).

Example 4b: Yield: 270 mg

¹H NMR (CDCl₃ 400 MHz): δ 7.54-7.45 (m, 4H), 6.25-6.23 (m, 1H),5.20-5.13 (m, 1H), 3.69-3.65 (m, 1H), 3.24 (d, J=3.2 Hz, 1H), 2.39-2.35(m, 1H), 2.27-2.21 (m, 1H), 1.49 (d, J=6.8 Hz, 3H), 0.91 (s, 9H).

LC-MS: t_(R)=2.48 min (LCMS Method 1), m/z=318.0 [M+H]⁺.

SFC: t_(R)=1.93 min (SFC Method 3), de=100%, [α]_(D) ²⁰=−61.4 (c=0.57g/100 mL, MeOH).

Example 8a: 3-Hydroxy-4,4-dimethyl-N— ((S)-1-(3-(trifluoro-methoxy)phenyl) propyl) pentanamide

and Example 8b: 3-Hydroxy-4,4-dimethyl-N— ((S)-1-(3-(trifluoro-methoxy)phenyl) propyl) pentanamide

Step 1: Preparation of3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

Prepared from Ve, Yield: 1.22 g

Step 2: Separation of(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamideand(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

3-Hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide was separated by flash chromatography on silica gel(Eluent of 0˜30% Ethyl acetate/petroleum ether gradient).

Example 8a: Yield: 0.51 g

¹H NMR (CDCl₃ 400 MHz): δ 7.40-7.34 (m, 1H), 7.25-7.21 (m, 1H),7.14-7.10 (m, 2H), 6.22-6.15 (m, 1H), 4.92 (q, J=7.6 Hz, 1H), 3.71-3.65(m, 1H), 3.21 (d, J=2.8 Hz, 1H), 2.40-2.23 (m, 2H), 1.82 (q, J=7.2 Hz,2H), 0.94-0.90 (m, 12H).

LC-MS: t_(R)=2.486 min (LCMS Method 5), m/z=348.0 [M+H]⁺.

SFC: t_(R)=1.775 min. (SFC Method 3), de=98.7%, [α]_(D) ²⁰=−80.0 (c=0.31g/100 mL, MeOH).

Example 8b: Yield: 0.59 g

¹H NMR (CDCl₃ 400 MHz): δ 7.39-7.33 (m, 1H), 7.25-7.20 (m, 1H),7.14-7.09 (m, 2H), 6.24 (br d, J=8.0 Hz, 1H), 4.92 (q, J=7.6 Hz, 1H),3.69-3.63 (m, 1H), 3.15 (d, J=3.2 Hz, 1H), 2.40-2.25 (m, 2H), 1.81 (q,J=7.6 Hz, 2H), 0.94-0.90 (m, 12H).

LC-MS: t_(R)=2.506 min (LCMS Method 5), m/z=348.0 [M+H]⁺.

SFC: t_(R)=1.609 min. (SFC Method 3) de=98.7%, [α]_(D) ²⁰=−40.0 (c=0.27g/100 mL, MeOH).

Example 11a: 3-(3,3-Difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl) propanamide

and Example 11b: 3-(3,3-Difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl) propanamide

Step 1: Preparation of3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

Prepared from V1. Yield: 300 mg, (60.7%).

Step 2: Separation of(S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propan-amideand(R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

Separated by chiral SFC.

Example 11a: Yield 90 mg

¹H NMR (400 MHz, CDCl₃) δ 7.42-7.35 (m, 1H), 7.25 (d, J=7.6 Hz, 1H),7.17-7.11 (m, 2H), 5.93 (d, J=7.2 Hz, 1H), 5.19-5.09 (m, 1H), 4.01-3.93(m, 1H), 3.86 (d, J=3.6 Hz, 1H), 2.62-2.48 (m, 3H), 2.46-2.13 (m, 4H),1.50 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=2.513 min (LCMS Method 2), m/z=368.0 [M+H]⁺.

SFC: t_(R)=2.169 min. (SFC method 3), de=97.4%, [α]_(D) ²⁰=−42.0 (c=2.0mg/mL, MeOH).

Example 11b: Yield 90 mg

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.36 (m, 1H), 7.25 (d, J=7.6 Hz, 1H),7.16-7.11 (m, 2H), 5.99 (d, J=7.2 Hz, 1H), 5.18-5.09 (m, 1H), 3.98 (t,J=7.2 Hz, 1H), 3.83 (br s, 1H), 2.61-2.49 (m, 3H), 2.45-2.12 (m, 4H),1.50 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=2.235 min (LCMS Method 3), m/z=368.0 [M+H]⁺.

SFC: t_(R)=2.013 min. (SFC Method 3), de=99.6%, [α]_(D) ²⁰=−17.0 (c=2.0mg/mL, MeOH).

Example 12a: 3-Hydroxy-4-methyl-N— ((S)-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl) pentanamide

and Example 12b: 3-Hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoro-ethoxy) phenyl)ethyl) pentanamide

Step 1: Preparation of3-Hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

Prepared from Vf.

Yield: 0.88 g (87%)

Step 2: Separation of(S)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamideand(R)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

3-Hydroxy-4-methyl-N— ((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide was separated by chiral SFC.

Example 12a: Yield: 0.362 g

¹H NMR (CDCl₃, 400 MHz) δ 7.31 (t, J=8.0 Hz, 1H), 7.01 (d, J=7.2 Hz,1H), 6.92 (t, J=2.0 Hz, 1H), 6.83 (dd, J=8.0, 2.4 Hz, 1H), 6.08 (br d,J=7.2 Hz, 1H), 5.12 (m, 1H), 4.36 (q, J=8.0 Hz, 2H), 3.80-3.74 (m, 1H),3.36 (d, J=3.2 Hz, 1H), 2.37-2.27 (m, 2H), 1.73-1.70 (m, 1H), 1.49 (d,J=6.8 Hz, 3H), 0.94 (dd, J=10.4, 6.8 Hz, 6H);

LC-MS: t_(R)=2.531 min (LCMS Method 2), m/z=334.0 [M+H]⁺.

SFC: t_(R)=2.864 min (SFC Method 3), de=99.2%, [α]_(D) ²⁰=−74.0 (c=0.20,MeOH).

Example 12b: Yield: 0.245 g

¹H NMR (CDCl₃, 400 MHz) δ 7.30 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.0 Hz,1H), 6.92 (t, J=2.0 Hz, 1H), 6.83 (dd, J=8.0, 2.4 Hz, 1H), 6.14 (br d,J=6.8 Hz, 1H), 5.11 (m, 1H), 4.36 (q, J=16.4, 8.0 Hz, 2H), 3.79-3.75 (m,1H), 3.34 (d, J=3.2 Hz, 1H), 2.38-2.25 (m, 2H), 1.73-1.62 (m, 1H), 1.49(d, J=7.2 Hz, 3H), 0.94 (dd, J=10.0, 6.8 Hz, 6H);

LC-MS: t_(R)=2.543 min (LCMS Method 2), m/z=334.0 [M+H]⁺.

SFC: t_(R)=3.071 min (SFC Method 3), de=99.7%, [α]_(D) ²⁰=−47.0 (c=0.20,MeOH).

Example 14a: 3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

and Example 14b: 3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

Step 1: Preparation of3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

Prepared from Vg.

Yield: 0.58 g

Step 2: Separation of(S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamideand(R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

3-(1-(difluoromethyl) cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide was separated byflash silica gel chromatography (Eluent of 0˜41% Ethyl acetate/petroleumether gradient).

Example 14a: 0.2 g

¹H NMR (CDCl₃ 400 MHz): δ 7.40-7.34 (m, 1H), 7.26-7.22 (m, 1H),7.16-7.11 (m, 2H), 6.11 (br d, J=7.2 Hz, 1H), 5.88 (t, J=58.4 Hz, 1H),5.12 (quin, J=7.2 Hz, 1H), 3.91 (d, J=3.2 Hz, 1H), 3.81-3.75 (m, 1H),2.62-2.48 (m, 2H), 1.49 (d, J=7.2 Hz, 3H), 0.87-0.76 (m, 2H), 0.76-0.62(m, 2H).

LC-MS: t_(R)=2.448 min (LCMS Method 1), m/z=368.0 [M+H]⁺.

SFC: t_(R)=2.282 min. (SFC Method 3), de=97.9%, [α]_(D) ²⁰=−62.0 (c=0.27g/100 mL, MeOH).

Example 14b: Yield: 0.18 g

¹H NMR (CDCl₃ 400 MHz): δ 7.40-7.34 (m, 1H), 7.24 (d, J=7.6 Hz, 1H),7.17-7.10 (m, 2H), 6.06 (br d, J=7.6 Hz, 1H), 5.84 (t, J=58.4 Hz, 1H),5.12 (quin, J=7.2 Hz, 1H), 3.86-3.79 (m, 2H), 2.55 (d, J=5.6 Hz, 2H),1.50 (d, J=6.8 Hz, 3H), 0.83-0.75 (m, 2H), 0.74-0.66 (m, 2H). LC-MS:t_(R)=2.467 min (LCMS Method 1), m/z=368.0 [M+H]⁺.

SFC t_(R)=1.960 min. (SFC Method 3), de=96.3%, [α]_(D) ²⁰=−54.4 (c=0.25g/100 mL, MeOH).

Example 16a: 3-Hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide

and Example 16b: 3-Hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide

Step 1: Preparation of3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide

Prepared from Vh and used directly in the next step.

Step 2: Separation of(R)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide and(S)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide

The crude product from step 1 was separated by chiral SFC to yield thedesired products.

Example 16a: Yield: 556 mg

¹H NMR (DMSO-d⁶ 400 MHz): δ 8.37 (d, J=7.6 Hz, 1H), 7.43-7.39 (m, 1H),7.31-7.29 (m, 1H), 7.23 (s, 1H), 7.18-7.16 (m, 1H), 5.21 (d, J=5.2 Hz,1H), 4.96-4.88 (m, 1H), 3.85-3.75 (m, 1H), 2.35-2.25 (m, 2H), 1.30 (d,J=7.2 Hz, 3H), 0.85-0.77 (m, 4H).

LC-MS: t_(R)=2.626 min (LCMS Method 2), m/z=386.0 [M+H]⁺.

SFC: t_(R)=2.010 min. (SFC Method 3), de=99.9%, [α]_(D) ²⁰=−56.0 (c=0.01g/100 mL, MeOH).

Example 16b: Yield: 692 mg

¹H NMR (DMSO-d⁶ 400 MHz): δ 8.36 (d, J=8.0 Hz, 1H), 7.42-7.38 (m, 1H),7.32 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 7.17-7.15 (m, 1H), 5.20 (d, J=5.2Hz, 1H), 4.95-4.91 (m, 1H), 3.75-3.85 (m, 1H), 2.25-2.35 (m, 2H), 1.30(d, J=6.8 Hz, 3H), 0.80-0.79 (m, 4H).

LC-MS: t_(R)=2.649 min (LCMS Method 2), m/z=386.0 [M+H]⁺.

SFC: t_(R)=1.615 min. (SFC Method 3), de=95.7%, [α]_(D) ²⁰=−46.0 (c=0.01g/100 mL, MeOH).

Example 20a: 3-Hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl) pentanamide

and Example 20b:3-Hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Step 1: Preparation of3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Prepared from Vi. Yield: 1.80 g (72%)

Step 2: Separation of(S)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamideand(R)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

3-Hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl) pentanamide was separated by chromatography (SiO₂, petroleum ether/ethylacetate=0:1 to 1:1)

Example 20a: 250 mg

¹H NMR (CDCl₃, 400 MHz) δ 7.37 (t, J=8.0 Hz, 1H), 7.27-7.21 (m, 1H),7.16-7.11 (m, 2H), 6.15 (d, J=6.8 Hz, 1H), 5.16 (quin, J=6.8 Hz, 1H),3.83-3.74 (m, 1H), 3.26 (d, J=3.2 Hz, 1H), 2.37 (dd, J=15.2, 3.2 Hz,1H), 2.31 (dd, J=15.2, 8.8 Hz, 1H), 1.74-1.68 (m, 1H), 1.50 (d, J=6.8Hz, 3H), 0.95 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=2.629 min (LCMS Method 2), m/z=320.0 [M+H]⁺.

SFC: t_(R)=2.404 min (SFC Method 13), de=98.6%, [α]_(D) ²⁰=−80.0(c=0.475 g/100 mL, MeOH).

Example 20b: Yield 470 mg

¹H NMR (CDCl₃, 400 MHz) δ 7.37 (t, J=7.6 Hz, 1H), 7.28-7.23 (m, 1H),7.16 (s, 1H), 7.14-7.11 (m, 1H), 6.19 (d, J=6.8 Hz, 1H), 5.15 (quin,J=7.2 Hz, 1H), 3.80-3.74 (m, 1H), 3.20 (d, J=3.6 Hz, 1H), 2.38 (dd,J=14.8, 2.4 Hz, 1H), 2.30 (dd, J=14.8, 9.2 Hz, 1H), 1.73-1.66 (m, 1H),1.49 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=2.654 min (LCMS Method 2), m/z=320.0 [M+H]⁺.

SFC: t_(R)=1.979 min (SFC Method 13), de=100%, [α]_(D) ²⁰=−52.0 (c=0.53g/100 mL, MeOH).

Example 21a: N—((R)-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

and Example 21b: N—((R)-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Step 1: Preparation ofN—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Prepared from Vj. Yield=350 mg, (96%)

Step 2: Separation ofN—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethyl-pentanamideandN—((R)-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-(S)-hydroxy-4,4-dimethylpentanamide

N—((R)-2-(Difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was separated by chiral SFC.

Example 21a: Yield: 98 mg

¹H NMR (CDCl₃ 400 MHz): δ 7.39 (t, J=8.0 Hz, 1H), 7.29-7.26 (m, 1H),7.20 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.65 (d, J=7.6 Hz, 1H), 6.22 (t,J=74.0 Hz, 1H), 5.34-5.30 (m, 1H), 4.18-4.09 (m, 2H), 3.69 (d, J=10.8Hz, 1H), 2.91 (s, 1H), 2.45-2.43 (m, 1H), 2.34-2.27 (m, 1H), 0.93 (s,9H).

LC-MS: t_(R)=2.471 min (LCMS Method 5), m/z=400.0 [M+H]⁺.

SFC: t_(R)=1.935 min (SFC Method 14), de=98.2%, [α]_(D) ²⁰=−2.4 (c=1.0g/100 mL, MeCN).

Example 21b: 160 mg

¹H NMR (DMSO-d⁶ 400 MHz): δ 8.54 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.0 Hz,1H), 7.41 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.67(t, J=76.0 Hz, 1H), 5.21-5.18 (m, 1H), 4.67 (s, 1H), 4.04-3.98 (m, 2H),3.53 (d, J=10.2 Hz, 1H), 2.31-2.26 (m, 1H), 2.19-2.12 (m, 1H), 0.82 (s,9H).

LC-MS: t_(R)=2.496 min (LCMS Method 5), m/z=400.0 [M+H]⁺.

SFC: t_(R)=2.461 min (SFC Method 14), de=97.1%, [α]_(D) ²⁰=−11.2 (c=1.0g/100 mL, MeCN).

Example 22a: 3-Hydroxy-N-[(1R)-2-methoxy-1-[3-(trifluoro-methoxy)phenyl]ethyl]-4,4-dimethyl-pentanamide

and Example 22b: 3-Hydroxy-N-[(1R)-2-methoxy-1-[3-(trifluoro-methoxy)phenyl]ethyl]-4,4-dimethyl-pentanamide

Step 1: Preparation of3-hydroxy-N-[(1R)-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-pentanamide

Prepared from Vk. Yield: 84 mg, (60%).

Step 2: Separation of(S)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamideand (R)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide

3-Hydroxy-N-[(1R)-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-pentanamidewas separated by chiral SFC.

Example 22a: Yield: 40 mg

¹H NMR (CDCl₃ 400 MHz): δ 7.35 (t, J=8.0 Hz, 1H), 7.27-7.26 (m, 1H),7.20 (s, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.66 (d, J=7.2 Hz, 1H), 5.18-5.14(m, 1H), 3.70-3.60 (m, 3H), 3.36 (s, 3H), 2.44 (d, J=14.8 Hz, 1H),2.25-2.33 (m, 1H), 0.93 (s, 9H)

LC-MS: t_(R)=2.410 min (LCMS Method 3), m/z=364.0 [M+H]⁺.

SFC: t_(R)=1.889 min (SFC Method 16), de=100%, [α]_(D) ²⁰=−0.4 (c=1.0g/100 mL, MeCN).

Example 22b: Yield: 38 mg

¹H NMR (CDCl₃ 400 MHz): δ 7.36 (t, J=8.0 Hz, 1H), 7.27-7.25 (m, 1H),7.18 (s, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.56 (d, J=7.2 Hz, 1H), 5.20-5.15(m, 1H), 3.69-3.60 (m, 3H), 3.40 (s, 1H), 3.36 (s, 3H), 2.44 (d, J=14.8Hz, 1H), 2.25-2.33 (m, 1H), 0.93 (s, 9H).

LC-MS: t_(R)=2.523 min (LCMS Method 1), m/z=364.0 [M+H]⁺.

SFC: t_(R)=2.106 min (SFC Method 16), de=98.2%, [α]_(D) ²⁰=−2.7 (c=1.0g/100 mL, MeCN).

Example 5:(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide

Step 1

A mixture of (1S)-1-[3-(trifluoromethoxy)phenyl]ethanamine hydrochloride(IIa) (291 mg, 1.20 mmol), 2-(3,3-difluoro-1-hydroxy-cyclobutyl)aceticacid (IIIb) (0.22 g, 1.32 mmol), HATU (549 mg, 1.44 mmol) and DIPEA (467mg, 3.6 mmol) in DCM (15 mL) was stirred at 20° C. for 16 hours. Themixture was washed with water (40 mL×2) and extracted with DCM (40 mL).The organic layer was washed with brine (10 mL×2), dried over Na₂SO₄ andconcentrated. The residue was purified by flash chromatography on silicagel (Eluent of 0˜35% Ethyl acetate/petroleum ether gradient) to give theproduct (0.2 g, 47% yield).

¹H NMR (CDCl₃, 400 MHz): δ 7.41-7.37 (m, 1H), 7.26-7.23 (m, 1H),7.18-7.13 (m, 2H), 5.93 (br d, J=6.8 Hz, 1H), 5.15 (quin, J=7.2 Hz, 1H),5.01 (br s, 1H), 2.84-2.42 (m, 6H), 1.53 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=2.53 min (LCMS Method 2), m/z=354.0 [M+H]⁺.

HPLC: t_(R)=13.3 min. (Chiral HPLC Method 1), de=100%. [α]²⁰ _(D)=−51.1(c=0.23 g/100 mL, MeOH).

The following examples were prepared by similar methodology to Example5, using the relevant staring materials:

Example 6:(S)-2-(1-Hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide

Step 1: Preparation of(S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide

Prepared from IIb (5.0 g, 22.81 mmol), and IIIa (3.3 g, 25.09 mmol).

Yield: 5.2 g, (45%).

¹H NMR (CDCl₃, 400 MHz): δ 7.29 (t, J=8.0 Hz, 1H), 6.99 (d, J=7.6 Hz,1H), 6.90 (s, 1H), 6.83 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.25 (d, J=6.8 Hz,1H), 5.14-5.07 (m, 1H), 4.35 (q, J=8.0 Hz, 2H), 4.14 (s, 2H), 2.53 (s,2H), 2.15-1.99 (m, 4H), 1.76 (m, 1H), 1.55 (m, 1H), 1.48 (d, J=6.8 Hz,3H).

LC-MS: t_(R)=2.49 min (LCMS Method 2), m/z=332.0 [M+H]⁺.

SFC: t_(R)=2.67 min (SFC Method 3), de=96.9%, [α]_(D) ²⁰=−69.0 (c=0.1,MeOH).

Example 7a:3-Hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)-3-(trifluoromethyl)pentanamide

and Example 7b:3-Hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)-3-(trifluoromethyl)pentanamide

Step 1: Preparation of3-Hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)-3-(trifluoromethyl)pentanamide

Prepared from IIb and IIIc. Yield: 0.65 g, (crude). The crude was useddirectly without purification.

Step 2: Separation of(3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide and(3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide

Separated by by flash silica gel chromatography (Eluent of 0˜15% Ethylacetate/petroleum ether gradient).

Example 7a: Yield: 0.29 g

¹H NMR (CDCl₃, 400 MHz): δ 7.32 (t, J=8.0 Hz, 1H), 7.00 (d, J=7.6 Hz,1H), 6.91 (d, J=2.0 Hz, 1H), 6.85 (dd, J=8.0, 2.4 Hz, 1H), 6.32 (s, 1H),5.99 (d, J=7.6 Hz, 1H). 5.15-5.07 (m, 1H), 4.36 (q, J=8.0 Hz, 2H), 2.45(d, J=15.2 Hz, 1H), 2.34 (d, J=15.2 Hz, 1H), 2.13-2.06 (m, 1H), 1.50 (d,J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=2.883 min (LCMS Method 4), m/z=402.0 [M+H]⁺.

SFC: t_(R)=2.454 min. (SFC Method 6), de=100%, [α]_(D) ²⁰=−43.5(c=0.0058 g/mL, MeOH).

Example 7b: Yield: 0.23 g

¹H NMR (CDCl₃, 400 MHz): δ 7.32 (t, J=8.0 Hz, 1H), 7.00 (d, J=7.6 Hz,1H), 6.91-6.84 (m, 2H), 6.33 (s, 1H), 5.90 (d, J=7.6 Hz, 1H), 5.19-5.10(m, 1H), 4.35 (q, J=8.4 Hz, 2H), 2.51 (d, J=14.8 Hz, 1H), 2.35 (d,J=14.8 Hz, 1H), 2.15-2.06 (m, 1H), 1.52 (d, J=7.2 Hz, 3H), 1.05 (d,J=6.8 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=2.834 min (LCMS Method 6), m/z=402.0 [M+H]⁺.

SFC: t_(R)=2.262 min. (SFC Method 7) de=99.8%, [α]_(D) ²⁰=−37.1(c=0.0034 g/mL, MeOH).

Example 9:4,4,4-Trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoro-methoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide

Step 1

Prepared from IIa and4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoic acid. Yield: 650mg, (63%)

¹H NMR (DMSO-d⁶ 400 MHz): δ 9.14 (d, J=7.2 Hz, 1H), 8.45 (s, 1H), 7.44(t, J=8.0 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.21 (d, J=8.4Hz, 1H), 5.01-4.93 (m, 1H), 2.89 (s, 2H), 1.34 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=2.850 min (LCMS Method 4), m/z=413.9 [M+H]⁺.

Chiral HPLC: t_(R)=15.61 min, (HPLC Method 2), de=98.4%, [α]_(D)²⁰=−41.1 (c=0.185 g/100 mL, MeOH)

Example 10a:4,4,5,5-Tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

and Example 10b:4,4,5,5-Tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Step1: Preparation of4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Prepared from IIa and IIId. Yield: 1 g (53%)

Step 2: Separation of(R)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamideand(S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

The diastereomers were separated by chiral SFC.

Example 10a: Yield=0.268 g

¹H NMR (CDCl₃ 400 MHz): δ 7.42-7.36 (m, 1H), 7.24 (d, J=7.6 Hz, 1H),7.17-7.12 (m, 2H), 6.28-5.97 (m, 2H), 5.93 (br d, J=6.0 Hz, 1H), 5.16(quin, J=6.8 Hz, 1H), 2.69 (d, J=15.2 Hz, 1H), 2.37 (d, J=15.2 Hz, 1H),1.53 (d, J=6.8 Hz, 3H), 1.40 (s, 3H).

LC-MS: t_(R)=2.759 min (LCMS Method 2), m/z=392.0 [M+H]⁺.

SFC: t_(R)=1.550 min. (SFC Method 15), de=100%, [α]_(D) ²⁰=−50.5 (c=0.19g/100 mL, MeOH).

Example 10b: Yield=0.148 g

¹H NMR (CDCl₃ 400 MHz): δ 7.44-7.36 (m, 1H), 7.26 (d, J=8.0 Hz, 1H),7.19-7.12 (m, 2H), 6.33-6.01 (m, 2H), 5.91 (br d, J=6.8 Hz, 1H), 5.16(quin, J=6.8 Hz, 1H), 2.70 (d, J=15.2 Hz, 1H), 2.35 (d, J=15.2 Hz, 1H),1.52 (d, J=6.8 Hz, 3H), 1.35 (s, 3H).

LC-MS: t_(R)=2.782 min (LCMS Method 2), m/z=392.0 [M+H]⁺.

SFC: t_(R)=1.329 min. (SFC Method 15), de=100%, [α]_(D) ²⁰=−48.6 (c=0.21g/100 mL, MeOH).

Example 13a:5,5,5-Trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxyphenyl)ethyl)pentanamide

and Example 13b:5,5,5-Trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Step 1: Preparation of5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Prepared from IIa and IIIe. Yield: 1 g, (43%)

Step 2: Separation of(R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamideand (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Separated by by flash chromatography on silica gel (Eluent of 0˜31%Ethyl acetate/petroleum ether gradient).

Example 13a: Yield=0.421 g

¹H NMR (CDCl₃ 400 MHz): δ 7.42-7.36 (m, 1H), 7.24 (d, J=8.0 Hz, 1H),7.17-7.12 (m, 2H), 5.98 (br d, J=6.8 Hz, 1H), 5.15 (quin, J=6.8 Hz, 1H),5.00 (s, 1H), 2.54-2.44 (m, 2H), 2.44-2.31 (m, 2H), 1.51 (d, J=7.2 Hz,3H), 1.38 (s, 3H),

LC-MS: t_(R)=2.666 min (LCMS Method 2), m/z=374.0 [M+H]⁺.

SFC: t_(R)=1.277 min. (SFC Method 8), de=100%, [α]_(D) ²⁰=−51.3 (c=0.23g/100 mL, MeOH).

Example 13b: 0.261 g

¹H NMR (CDCl₃ 400 MHz): δ 7.42-7.36 (m, 1H), 7.25 (d, J=8.0 Hz, 1H),7.17-7.12 (m, 2H), 5.96 (br d, J=7.2 Hz, 1H), 5.16 (quin, J=6.8 Hz, 1H),4.98 (s, 1H), 2.57-2.36 (m, 4H), 1.52 (d, J=6.8 Hz, 3H), 1.36 (s, 3H),

LC-MS: t_(R)=2.674 min (LCMS Method 2), m/z=374.0 [M+H]⁺.

SFC: t_(R)=1.197 min. (SFC Method 8), de=93.4%, [α]_(D) ²⁰=−43.2 (c=0.19g/100 mL, MeOH).

Example 15a:3-(1-Fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide

and Example 15b:3-(1-Fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide

Step 1: Preparation of3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide

Prepared from IIa and IIIf. The crude was used directly in the next step

Step 2: Separation of(R)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamideand(S)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamide

Separated by flash chromatography on silica gel (Eluent of 0˜30% Ethylacetate/petroleum ether gradient).

Example 15a: Yield=1.05 g

¹H NMR (CDCl₃ 400 MHz): δ 7.37 (t, J=8.0 Hz, 1H), 7.27-7.24 (m, 1H),7.17-7.12 (m, 2H), 6.11 (br s, 1H), 5.18-5.10 (m, 1H), 5.02 (s, 1H),2.61 (dd, J=14.4, 2.4 Hz, 1H), 2.46 (dd, J=14.4, 1.6 Hz, 1H), 1.51 (d,J=7.2 Hz, 3H), 1.33 (s, 3H), 0.78-0.68 (m, 3H), 0.52-0.50 (m, 1H).

LC-MS: t_(R)=2.359 min (LCMS Method 3), m/z=350.0 [M+H]⁺.

SFC: t_(R)=2.027 min. (SFC Method 9), de=93.9%, [α]_(D) ²⁰=−48.3 (c=0.24g/100 mL, MeOH).

Example 15b: Yield: 0.80 g

¹H NMR (CDCl₃ 400 MHz): δ 7.38 (t, J=8.0 Hz, 1H), 7.27-7.23 (m, 1H),7.15-7.12 (m, 2H), 6.06 (d, J=7.2 Hz, 1H), 5.19-5.11 (m, 1H), 4.99 (s,1H), 2.62 (dd, J=14.4, 2.0 Hz, 1H), 2.47 (d, J=1.6 Hz, 1H), 2.43 (d,J=1.6 Hz, 1H), 1.51 (d, J=7.2 Hz, 3H), 1.33 (s, 3H), 0.97-0.87 (m, 1H),0.85-0.81 (m, 3H).

LC-MS: t_(R)=2.655 min (LCMS Method 2), m/z=350.0 [M+H]⁺.

SFC: t_(R)=1.937 min. (SFC Method 9), de=98.7%, [α]_(D) ²⁰=−64.4 (c=0.27g/100 mL, MeOH).

Example 17:(R)-2-(1-Hydroxycyclopentyl)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide

Prepared from IIa and 2-(1-hydroxycyclopentyl)acetic acid.

Yield: 30 mg, (12.8%).

¹H NMR (400 MHz, CDCl₃) δ 7.37 (t, J=8.0 Hz, 1H), 7.26-7.25 (m, 1H),7.19 (s, 1H), 7.16-7.11 (m, 1H), 6.66 (br d, J=7.2 Hz, 1H), 5.21-5.15(m, 1H), 3.82 (s, 1H), 3.70-3.60 (m, 2H), 3.37 (s, 3H), 2.59-2.49 (m,2H), 1.86-1.81 (m, 4H), 1.59-1.56 (m, 4H).

LC-MS: t_(R)=2.481 min (LCMS Method 2), m/z=362.0 [M+H]⁺,

SFC: t_(R)=2.33 min. (SFC Method 10), de=100%, [α]_(D) ²⁰=−44.0, (c=1mg/mL, MeOH).

Example 18a:3-Cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

and Example 18b:3-Cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

Step 1: Preparation of3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

Prepared from IIb and IIIg. Yield: 3.7 g, (30.9%)

Step 2: Separation of(R)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamideand(S)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

Separated by chiral SFC.

Example 18a: Yield: 1.59 g

¹H NMR (400 MHz, DMSO-d₆) b 8.32 (d, J=8.0 Hz, 1H), 7.28 (t, J=8.0 Hz,1H), 7.04-6.98 (m, 2H), 6.93-6.90 (m, 1H), 4.97-4.91 (m, 1H), 4.73 (q,J=8.8 Hz, 2H), 4.61 (s, 1H), 2.37-2.25 (m, 2H), 1.34 (d, J=7.2 Hz, 3H),1.10 (s, 3H), 0.87-0.84 (m, 1H), 0.30-0.09 (m, 4H).

LC-MS: t_(R)=2.629 min (LCMS Method 2), m/z=328.0 [M+H−18]⁺.

SFC: t_(R)=3.154 min (SFC Method 11), de=99.7%, [α]_(D) ²⁰=−62.0 (c=2mg/mL, MeOH)

Example 18b: Yield: 1.44 g

¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (br d, J=8.0 Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 6.87-6.79 (m, 2H), 6.77-6.74 (m, 1H), 4.81-4.73 (m, 1H), 4.57(q, J=8.8 Hz, 2H), 4.42 (s, 1H), 2.19-2.08 (m, 2H), 1.17 (d, J=6.8 Hz,3H), 0.94 (s, 3H), 0.73-0.64 (m, 1H), 0.19-0.00 (m, 4H).

LC-MS: t_(R)=2.643 min (LCMS Method 2), m/z=328.0 [M+H−18]⁺.

SFC: t_(R)=2.570 min. (SFC Method 11), de=97.0%, [α]_(D) ²⁰=−58.0 (c=2mg/mL, MeOH)

Example 19a:4,4,4-Trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

and Example 19b:4,4,4-Trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

Step 1: Preparation of4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

Prepared from IIb and 4,4,4-trifluoro-3-hydroxy-3-methyl-butanoic acid.Yield: 6.67 g, (73%)

Step 2: Separation of(R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy))ethyl)butanamideand (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

Example 19a: 2.3 g

¹H NMR (CDCl₃, 400 MHz) δ 7.32 (t, J=8.0 Hz, 1H), 6.99 (d, J=7.8 Hz,1H), 6.92-6.88 (m, 1H), 6.88-6.83 (m, 1H), 5.99 (br d, J=6.8 Hz, 1H),5.84 (s, 1H), 5.12 (quin, J=7.2 Hz, 1H), 4.35 (q, J=8.0 Hz, 2H), 2.51(dd, J=53.2, 15.2 Hz, 2H), 1.51 (d, J=7.2 Hz, 3H), 1.41 (s, 3H); LC-MS:t_(R)=2.732 min (LCMS Method 2), m/z=374.0 [M+H]⁺.

SFC: t_(R)=1.721 min (SFC Method 12), de=99.6%, [α]_(D) ²⁰=−51.0(c=0.20, MeOH).

Example 19b: 0.86 g

¹H NMR (CDCl₃, 400 MHz) δ7.33 (t, J=8.0 Hz, 1H), 7.00 (d, J=7.2 Hz, 1H),6.93-6.90 (m, 1H), 6.88-6.83 (m, 1H), 5.98-5.91 (m, 1H), 5.91 (s, 1H),5.12 (quin, J=7.2 Hz, 1H), 4.36 (q, J=8.0 Hz, 2H), 2.50 (dd, J=57.6,14.8 Hz, 2H), 1.51 (d, J=6.8 Hz, 3H), 1.39 (s, 3H);

LC-MS: t_(R)=2.737 min (LCMS Method 2), m/z=374.0 [M+H]⁺.

SFC: t_(R)=1.904 min (SFC Method 12), de=100%, [α]_(D) ²⁰=−57.1 (c=0.21,MeOH).

1-10. (canceled)
 11. A method of treating a patient in the need thereofsuffering from psychosis, mania, stress-related disorders, acute stressreactions, bipolar depression, major depression, anxiety, panic attacks,social phobia, sleep disturbances, ADHD, PTSD, OCD, impulsivitydisorders, personality disorders, schizotypical disorder, aggression,chronic pain, neuropathy, autism spectrum disorders, Huntingtons chorea,sclerosis, multiple sclerosis, or Alzheimer's disease, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I):

wherein R1 is selected from the group consisting of C₁-C₆ alkyl, CF₃,CH₂CF₃, CF₂CHF₂, and C₃-C₈ cycloalkyl, wherein said C₃-C₈ cycloalkyl maybe substituted with 1 or 2 F, CHF₂ or CF₃, and R2 is H, C₁-C₆ alkyl orCF₃; or R1 and R2 combine to form C₃-C₅ cycloalkyl optionallysubstituted with 1 or 2 F, CHF₂ or CF₃; R3 is C₁-C₃ alkyl orCH₂O—C₁₋₃alkyl, wherein said C₁-C₃ alkyl or CH₂O—C₁₋₃ alkyl mayoptionally substituted with 1 or 2 F; and R4 is selected from the groupconsisting of CF₃, OCF₃, OCH₂CF₃ and OCHF₂. 12-16. (canceled)
 17. Themethod of claim 11, wherein R4 is is OCF₃ or OCHF₂.
 18. The method ofclaim 11, wherein R2 is H or CH₃.
 19. The method of claim 11, wherein R3is CH₂O—C₁₋₃ alkyl.
 20. The method of claim 11, wherein R1 is C₃-C₄cycloalkyl optionally substituted with 1 or 2 F, CHF₂ or CF₃.
 21. Themethod of claim 11, wherein R1 is t-butyl and R2 is H and R4 is OCF₃,OCH₂CF₃, OCHF₂ or CF₃.
 22. The method of claim 11, wherein R1 and R2combine to form cyclobutyl optionally substituted with 1 or 2 F and R4is OCF₃, OCH₂CF₃, OCHF₂ or CF₃.
 23. The method of claim 11, wherein thecompound is selected from the group consisting of:(S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,(S)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,(R)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide,(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide,(S)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,(R)-3-hydroxy-4,4-dimethyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,(S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,(R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,(S)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,(R)-3-hydroxy-4-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,(S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)propanamide,(R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide,(R)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,(S)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,(S)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,(R)-3-hydroxy-4-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethylpentanamide,N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(S)-hydroxy-4,4-dimethylpentanamide,(S)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide,(R)-3-hydroxy-N—((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide,(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,(S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide,(3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,(3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,4,4,4-Trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide,(R)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,(S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,(R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,(S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,(R)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide,(S)-3-(1-fluorocyclopropyl)-3-hydroxy-N—((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamide,(R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,(R)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,(S)-3-cyclopropyl-3-hydroxy-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,(R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,and(S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N—((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide.